Dr Nicolas Jonckheere
email: nicolas.jonckheere@inserm.fr

Nicolas Skrypek

Isabelle Van Seuningen

Mucins and tumor resistance to chemotherapeutic drugs

Keywords: mucin, cancer, resistance, chemotherapeutic drug, apoptosis, prognosis biomarker

Epithelial cancer patients that are not considered eligible for surgical resection frequently benefit from chemotherapy. Chemotherapy is the treatment of cancer with one or combination of cytotoxic or cytostatic drugs. Recent advances in chemotherapy allowed a great number of cancer patients to receive treatment with significant results. Unfortunately, resistance to chemotherapeutic drug treatment is a major challenge for clinicians in the majority of epithelial cancers because it is responsible for the inefficiency of therapies.

Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Implications of mucins have been described in relation to cancer cell behavior and cell signaling pathways associated with epithelial tumorigenesis. Because of the frequent alteration of the pattern of mucin expression in cancers as well as their structural and functional characteristics, mucins are thought to also be involved in response to therapies. In this report, we review the roles of mucins in chemoresistance and the associated underlying molecular mechanisms (physical barrier, apoptosis resistance, drug catabolism or exclusion, cell stemness, epithelial mesenchymal transition) and discuss the therapeutic tools/strategies and/or prognosis biomarkers for personalized chemotherapy response that could be proposed from these studies.

Introduction

Mucins belong to an heterogeneous group of large O-glycoproteins composed of a long peptidic chain (called apomucin) on which are linked hundreds of oligosaccharidic chains.

Initially, the mucin word designated glycoproteins secreted by specialized epithelial cells, the goblet cells, as part of the mucus gel. Mucins were biochemically characterized as massive molecules with high molecular weight able to form viscoelastic gels and responsible for the rheological properties of mucus [START_REF] Roussel | The complexity of mucins[END_REF]. The molecular era that led to genome sequencing allowed the classification of two sub-groups of mucins: (i) secreted mucins that mostly complied with this definition and (ii) membrane-bound or transmembrane mucins that did not fit in. Despite this dichotomy, mucins were all included in the MUC family with the approval of Human Genome Organization Gene Nomenclature Committee (HUGO/GNC) [START_REF] Dekker | The MUC family: an obituary[END_REF].

Secreted mucins are the major components of viscoelastic mucus gels and form a tridimensional network that protects the epithelia against various agression (inflammation, bacteria, virus, pollutants, pH, etc). This subgroup mainly includes: MUC2, MUC5AC, MUC5B, MUC6 (clustered on the p15 arm of chromosome 11) and MUC19. MUC7 and MUC9 are smaller secreted mucins that do not oligomerize and are secreted by specialized cells as monomers [START_REF] Gendler | Epithelial mucin genes[END_REF][START_REF] Thornton | Structure and function of the polymeric mucins in airways mucus[END_REF][START_REF] Desseyn | Architecture of the gel-forming mucins[END_REF]. Secreted mucins comprise amino (N-t) and carboxyl terminal (C-t) regions sharing structural domains with von Willebrand (vW) factor. The central part is enriched in Pro, Thr and Ser amino acid residues forming the variable PTS domain that is Oglycosylated [START_REF] Thornton | Structure and function of the polymeric mucins in airways mucus[END_REF]. The O-glycosylation process is crucial for mucin secretion, stability, processing, and functions during both development and pathophysiological conditions [START_REF] Baldus | MUC1 and the MUCs: a family of human mucins with impact in cancer biology[END_REF][START_REF] Tran | Mucin-type O-glycosylation during development[END_REF][START_REF] Groux-Degroote | Biosynthesis of mucin O-glycan chains in normal and pathological states[END_REF].

The adjacent CYS domains are highly hydrophobic and are believed to cause the aggregation of mucins [START_REF] Desseyn | Mucin CYS domains are ancient and highly conserved modules that evolved in concert[END_REF]. By forming disulfide bonds, the main intestinal mucin MUC2 dimerizes via its C-terminal cysteine-knot (CK) domain and also trimerizes via N-t vWD domains building a complex molecular network [START_REF] Ambort | Perspectives on mucus properties and formation--lessons from the biochemical world[END_REF][START_REF] Backstrom | Increased understanding of the biochemistry and biosynthesis of MUC2 and other gel-forming mucins through the recombinant expression of their protein domains[END_REF]. On the contrary MUC5AC and MUC5B are linear disulfide-linked polymers that polydisperse and that behave as random coils in solution [START_REF] Thornton | Structure and function of the polymeric mucins in airways mucus[END_REF] The membrane-bound mucins are type I membrane-anchored proteins including MUC1, MUC3, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC20, MUC21 and MUC22 [START_REF] Hattrup | Structure and function of the cell surface (tethered) mucins[END_REF][START_REF] Jonckheere | Membrane-bound mucin modular domains: from structure to function[END_REF][START_REF] Jonckheere | The membrane-bound mucins: how large O-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies[END_REF]. Typically, membrane-bound mucins contain a long extracellular domain, a hydrophobic transmembrane domain, and a short cytoplasmic tail. Analysis of the peptidic sequences of mucins allowed description of their modular organization. The PTS domain, the only domain not conserved at the genomic level, is the common feature between mucins.

Membrane-bound mucins share conserved domains such as epidermal growth factor-like (EGF) or Sea urchin sperm protein Enterokinase and Agrin (SEA) domains [START_REF] Jonckheere | Membrane-bound mucin modular domains: from structure to function[END_REF][START_REF] Desseyn | Architecture of the large membrane-bound mucins[END_REF][START_REF] Perez | Focus on Molecules: human mucin MUC16[END_REF].

Based on their structure and localization at the cell surface they were shown to act in cell-cell, cell-extracellular matrix interactions and in cell signaling.

Mucins have a cell-and tissue-specific patterns of expression profoundly altered in epithelial cancers (loss of expression, over-expression, aberrant expression, neo-expression, glycosylation alterations) [START_REF] Jonckheere | The membrane-bound mucins: From cell signalling to transcriptional regulation and expression in epithelial cancers[END_REF][START_REF] Van Seuningen | Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer?[END_REF][START_REF] Pinto | Identification of new cancer biomarkers based on aberrant mucin glycoforms by in situ proximity ligation[END_REF][START_REF] Robbe-Masselot | Tumour-associated antigens of mucin O-glycans. Clinical relevance of glycobiology in cancer and inflammatory diseases of the epithelium[END_REF][START_REF] Argueso | Assessing mucin expression and function in human ocular surface epithelia in vivo and in vitro[END_REF]. Because of their specific pattern of expression during the different steps of tumor progression toward adenocarcinoma, mucins stay under intense investigation as both potent new biomarkers and therapeutic targets in epithelial cancers.

Numerous reviews in the literature describe the roles of mucins in relation to cancer cell behavior and cell signaling pathways associated with tumorigenesis. Among them, membrane-bound mucins MUC1 and MUC4 have been extensively studied [START_REF] Jonckheere | The membrane-bound mucins: how large O-glycoproteins play key roles in epithelial cancers and hold promise as biological tools for gene-based and immunotherapies[END_REF][START_REF] Hollingsworth | Mucins in cancer: protection and control of the cell surface[END_REF][START_REF] Jonckheere | Mucins and pancreatic cancer[END_REF][START_REF] Kaur | Mucins in pancreatic cancer and its microenvironment[END_REF][START_REF] Kufe | Mucins in cancer: function, prognosis and therapy[END_REF].

MUC1 and MUC4 govern both cellular differentiation and proliferation. They are also involved in metastasis and tumor proliferation. Secreted mucins MUC5B and MUC5AC and membrane bound mucins MUC13 and MUC16 have also been associated with aggressive behavior of cancer cells [START_REF] Hoshi | Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer[END_REF][START_REF] Valque | MUC5B leads to aggressive behavior of breast cancer MCF7 cells[END_REF][START_REF] Yamazoe | RNA interference suppression of mucin 5AC (MUC5AC) reduces the adhesive and invasive capacity of human pancreatic cancer cells[END_REF][START_REF] Chauhan | MUC13 mucin augments pancreatic tumorigenesis[END_REF][START_REF] Maher | Mucin 13: structure, function, and potential roles in cancer pathogenesis[END_REF][START_REF] Lakshmanan | MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells[END_REF]. On the contrary, Muc2 is involved in the suppression of colorectal cancer (CRC) since Muc2 KO mice develop adenoma progress with age to invasive adenocarcinoma in the small intestine [START_REF] Velcich | Colorectal cancer in mice genetically deficient in the mucin Muc2[END_REF].

The dramatic outcome of epithelial cancers of the gastrointestinal tract is often related to a lack of efficient therapeutic tools and early diagnostic markers. Patients that are not considered eligible for surgical resection frequently benefit from chemotherapy. However, chemoresistance is a common feature of epithelial cancers. Lately, mucins have been proposed as actors of this phenomenon. In this review, we will discuss their role and the associated cellular mechanisms in chemoresistance in order to propose them as therapeutic tools and/or prognosis biomarkers of chemotherapy response.

Mucins and chemoresistance in vitro

In our laboratory and others, initial in vitro studies showing the relationship between mucin and chemoresistance came from colorectal carcinoma cells (HT29) stably resistant to 5fluorouracil or methotrexate [START_REF] Dahiya | Expression and characterization of mucins associated with the resistance to methotrexate of human colonic adenocarcinoma cell line HT29[END_REF][START_REF] Lesuffleur | Differential expression of the human mucin genes MUC1 to MUC5 in relation to growth and differentiation of different mucus-secreting HT-29 cell subpopulations[END_REF][START_REF] Leteurtre | Differential mucin expression in colon carcinoma HT-29 clones with variable resistance to 5fluorouracil and methotrexate[END_REF]. These cells were characterized by the overexpression of secreted mucins when they became resistant cells. This observation pointed out to the potential of mucins as actors of chemoresistance (Table I).

In breast cancer cells, the overexpression of MUC1 is involved in cell sensitivity to Herceptin® via the increase of the cleavage of this mucin. These cells are also resistant to paclitaxel (Taxol®), doxorubicin and cyclophosphamide, suggesting a broader involvement of membrane-bound mucins [START_REF] Fessler | MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells[END_REF]. Similarly, silencing the MUC1 or MUC4 gene can reverse resistance to trastuzumab in HER2-positive gastric cancers [START_REF] Deng | Effect of MUC1 siRNA on drug resistance of gastric cancer cells to trastuzumab[END_REF][START_REF] Shi | Catecholamine-Induced beta2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression[END_REF].

Xenograft tumors of estrogen receptor positive (ER)/HER2-overexpressing breast cancer cells, that are developing resistance to lapatinib and trastuzumab, harbor an increase in mucinfilled vacuoles and upregulation of several mucins including MUC4 [START_REF] Chen | Upregulation of mucin4 in ERpositive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies[END_REF] suggesting a role of MUC4 in acquired resistance to chemotherapy. MUC4 influence on chemosensitivity has been studied in pancreatic cancer cells using gain or loss of function strategies. Several reports showed that MUC4 protects pancreatic cancer cells from gemcitabine-induced cytotoxicity [START_REF] Bafna | Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin[END_REF][START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF][START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF][START_REF] Wissniowski | Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells[END_REF]. Similar observation was made regarding another cytidine analog, the cytarabine/aracytin ARA-C [START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF] or 5-fluoro-uracile (unpublished data). Overexpression of rat orthologue MUC4/SMC in melanoma cells also reverts antiproliferative effect of taxol, doxorubicin, vinblastine, rhodamine-123 or 2-deoxyglucose and cell death induced by doxorubicin [START_REF] Hu | Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells[END_REF]. Finally MUC4 expression was also shown to reduce the mitochondrial damage in pancreatic cancer cells induced by the inhibition of the proteasome when treated by the boronic acid derivative bortezomib [START_REF] Wissniowski | Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells[END_REF].

Mucins and clinical response to chemotherapy

Mucinous tumors

Retrospective clinical studies indicate that mucinous carcinoma or adenocarcinoma (uterine, colorectal or breast cancer), characterized by an abundant mucus gel covering the tumor, are less sensitive to neoadjuvant chemotherapies and radiotherapies. These data support that a link exist between the mucus and chemotherapeutic efficiency in the tumor context [START_REF] Mekenkamp | Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer[END_REF][START_REF] Nagao | The differences in the histological types of breast cancer and the response to neoadjuvant chemotherapy: the relationship between the outcome and the clinicopathological characteristics[END_REF][START_REF] Oberholzer | Rectal cancer: mucinous carcinoma on magnetic resonance imaging indicates poor response to neoadjuvant chemoradiation[END_REF][START_REF] Poujade | Pathologic response rate after concomitant neo-adjuvant radiotherapy and chemotherapy for adenocarcinoma of the uterine cervix: a retrospective multicentric study[END_REF].

In advanced gastric cancer, the signet ring cell (SRC) histologic subtype, characterized by cells containing a large mucus vacuole, is an independent predictor of poor prognosis. Moreover, perioperative chemotherapy provides no benefit on survival [START_REF] Messager | The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study[END_REF]. However, the direct involvements of secreted mucins in these clinical observations, as well as the associated underlying cellular mechanisms, remain to be determined.

Non-mucinous tumors

On the contrary, a fair number of studies have shown that tumors expressing MUC1 exhibit an increased capacity to resist the effects of chemotherapeutic drugs in breast and ovarian cancers. Frequency analysis of MUC1 expression in an important cohort of 691 breast cancer biopsies showed that both MUC1 mRNA and protein high expression was associated with lower probability of complete response to neoadjuvant chemotherapy [START_REF] Sinn | Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer[END_REF]. MUC1 regulates cholesterol and fatty acid metabolism in human breast cancer. Activation of these pathways in ER(+) breast cancers predicts failure to tamoxifen treatment with higher risk for death and recurrence/distant metastasis [START_REF] Pitroda | MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment[END_REF].

MUC1 protein level is significantly increased in platinum resistant ovarian tumors compared to those in sensitive-group because of chromosomal amplifications of 1q21-q22 [START_REF] Takano | Amplicon profiling reveals cytoplasmic overexpression of MUC1 protein as an indicator of resistance to platinum-based chemotherapy in patients with ovarian cancer[END_REF]. A follow-up analysis of 92 ovarian cancer patient cohort also showed that the increase of MUC1 expression is a significant risk factor for chemoresistance to taxane combined platinum-based drugs in patients with ovarian epithelial cancer [START_REF] Zhang | Chemoresistance Is Associated with MUC1 and Lewis y Antigen Expression in Ovarian Epithelial Cancers[END_REF].

Mucins form a physical barrier

The outstanding web formed by the secreted mucus as well as the extraordinary size of heavily glycosylated membrane-bound mucins such as MUC1, MUC4 or MUC16 (>10 6 Da) suggest that mucins are capable to limit (i) drug intracellular entrance and/or (ii) the accessibility of the plasma membrane and its tumor cell epitopes for immune recognition or antibody-based therapy (Figure 1A).

Because of the viscosity/rheology of the mucus, secreted mucins may stop poorly soluble drugs diffusion through the cell membrane. In diseases characterized by dense mucus such as chronic inflammatory cystic fibrosis, the mucus permeability is also decreased making the diffusion more difficult for therapeutics molecules [START_REF] Bhat | Drug diffusion through cystic fibrotic mucus: steadystate permeation, rheologic properties, and glycoprotein morphology[END_REF]. Two functions are hypothesized:

Either mucins act as size filters and allow the entrance of drugs smaller than mucus network holes, or they act as interaction filters via electrostatic or hydrophobic forces accordingly to their surface properties and independently of drug molecular size [START_REF] Sigurdsson | Mucus as a barrier to lipophilic drugs[END_REF] as ionisation of the drug was shown to influence its diffusion through mucus [START_REF] Shaw | The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus[END_REF]. The size, the electric charge and the hydrophilic property of mucins molecules composing the mucus is critical for the permeability. The electronegative potential of mucins, mostly carried by sialic acids on Oglycosidic chains, could affect the interaction affinity of mucus [START_REF] Robbe-Masselot | Tumour-associated antigens of mucin O-glycans. Clinical relevance of glycobiology in cancer and inflammatory diseases of the epithelium[END_REF] and can create electrostatic interactions with positively charged molecules (as amikacin or gemcitabine) decreasing their diffusion [START_REF] Khanvilkar | Drug transfer through mucus[END_REF]. antiproliferative activity [START_REF] Kalra | Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain[END_REF]. Benzyl-α-GalNAc that leads to a storage phenotype and abnormal intracellular localization of apical glycoproteins, does not alter directly mucin expression in CAPAN-1 cells since it was previously shown that MUC1 kept its normal localization [START_REF] Leteurtre | Induction of a storage phenotype and abnormal intracellular localization of apical glycoproteins are two independent responses to GalNAcalpha-O-bn[END_REF]. Therefore, Kalra and Campbell speculated that the inhibition of mucin glycosylation may reduce the formidable mucin O-glycosylation mesh and facilitate the entrance of chemotherapeutic drug [START_REF] Kalra | Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain[END_REF]. In this model, the mucin network is thought to limit the intracellular uptake of 5-FU and to attenuate its chemotherapeutic effect independently of sialic acid [START_REF] Kalra | Mucin overexpression limits the effectiveness of 5-FU by reducing intracellular drug uptake and antineoplastic drug effects in pancreatic tumours[END_REF]. The mucus layer on the surface of normal epithelial cells was also shown to limit the diffusion of nutrients and small molecules depending on their size and physicochemical properties [START_REF] Lafitte | Diffusion of nutrients molecules and model drug carriers through mucin layer investigated by magnetic resonance imaging with chemical shift resolution[END_REF].

The overexpression of the high-molecular weight glycoprotein membrane-bound mucins on the target tumor cell surface can mask the surface antigens, and thereby decrease their accessibility and the cytotoxic response induced by antibody-based therapy as well as the tumor cell killing mediated by immune cells. It has been shown that overexpression of rMuc4, MUC1 or MUC16 can create an immunosuppressive barrier by decreasing the accessibility of immune cells (as lymphokine-activated killer cell) to antigenic epitope dependent on Oglycosylation length [START_REF] Gubbels | MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells[END_REF][START_REF] Komatsu | Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells[END_REF][START_REF] Van De Wiel-Van Kemenade | Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction[END_REF]. The overexpression membrane-bound mucins block drug accessibility to therapeutic targets such as oncogenic receptors EGFR, ErbB2, VEGFR targeted by Erbitux/Cetuximab, Herceptin/trastuzumab, Avastin/Bevacizumab, respectively.

The overexpression of rMuc4 in pancreatic cancer cell has been shown to decrease the recognition and thus the efficiency of the monoclonal antibody trastuzumab (Herceptin) which targets the oncogenic receptor ErbB2 [START_REF] Price-Schiavi | Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance[END_REF]. A converse correlation has been established between the expression of MUC4 and Herceptin sensitivity in mammary cancer cells. The JIMT-1 cell line expressing the highest level of MUC4 is highly resistant to this monoclonal antibody [START_REF] Nagy | Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line[END_REF].

Resistance to apoptosis

The induction of apoptosis is the main goal of all cytotoxic therapy. Programmed cell death resistance is a major cause of chemoresistance in which expression of mucins can reduce the sensitivity of cancer cells to genotoxic drugs by decreasing the apoptotic effect following DNA damages or physiologic stress (Figure 1B).

MUC1

MUC1 role as an apoptotic inhibitor in cancer cells is well-documented (Figure 2). Indeed, MUC1 decreases apoptotic mitochondrial factors release, caspase-3 activation, and subsequent apoptosis induction in CRC cells treated with the genotoxic agent cisplatine [START_REF] Ren | Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents[END_REF].

MUC1 cytoplasmic tail (MUC1-CT) inhibits the activation of a large array of intrinsic apoptotic pathways by regulating different signaling pathways such as p53, FOXO3a, c-Abl, IB complex, FADD or Bax. MUC1-CT interacts with p53 tumor suppressor on its responsive elements to coactivate p21 at the transcriptional level. On the contrary, MUC1 attenuates Bax transcription [START_REF] Wei | Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response[END_REF]. MUC1-CT also associates with Bax in the cytoplasm and the mitochondria via their CQC motif and BH3 domains, respectively, and blocks Bax dimerisation and subsequent cytochrome c release that normally activate the mitochondrial death pathway [START_REF] Ahmad | The MUC1-C oncoprotein binds to the BH3 domain of the pro-apoptotic BAX protein and blocks BAX function[END_REF]. MUC1-CT anti-apoptotic function is also mediated via c-Abl sequestration within the cytoplasm and blocking of c-Abl and cytosolic 14-3-3 interaction [START_REF] Raina | MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage[END_REF]. Mutation of MUC1-CT at Tyr 60 (Y60F) disrupts the MUC1-Abl interaction inducing ARF expression and inhibiting MDM2-p53 pathway [START_REF] Raina | MUC1 oncoprotein suppresses activation of the ARF-MDM2-p53 pathway[END_REF]. MUC1 is important for physiological activation of IB kinase- (IKK) complex and sustained activation of NF-B pathway in response to TNF- activation [START_REF] Ahmad | MUC1 oncoprotein activates the IkappaB kinase beta complex and constitutive NF-kappaB signalling[END_REF]. In response to TNF-, MUC1-CT also interacts with caspase-8 and Fas-associated death domain following death receptor stimulation and block the activation of apoptosis process [START_REF] Agata | MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8[END_REF]. In clear renal cell carcinoma (cRCC), overexpression of MUC1 prevents anoïkis through anti-apoptotic NF-B nuclear localization, caspase-9 expression and the increase of Bcl XL /Bax ratio [START_REF] Bouillez | MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway[END_REF].

Normal cellular metabolism is associated with the production of reactive oxygen species (ROS) including superoxide ion (O 2 -), hydrogen peroxide (H 2 O 2 ), hydroxyl radicals, and nitric oxide. Increase in ROS levels can cause damage to DNA, proteins, and lipids [START_REF] Lau | Reactive oxygen species: current knowledge and applications in cancer research and therapeutic[END_REF][START_REF] Storz | Reactive oxygen species in tumor progression[END_REF].

MUC1 reduces apoptosis following oxidative stress by regulating endogenous and H 2 O 2induced intracellular levels of ROS. Reciprocally, MUC1 expression is up-regulated by oxidative stress at the transcriptional level [START_REF] Yin | Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress[END_REF]. MUC1-CT also induces FOXO3a activation and attenuates the oxidative stress in colon and breast cancer cells [START_REF] Yin | MUC1 oncoprotein activates the FOXO3a transcription factor in a survival response to oxidative stress[END_REF]. Chronic ROS exposure leads to HIF-1 stabilization and up-regulation of downstream target genes [START_REF] Fruehauf | Reactive oxygen species: a breath of life or death?[END_REF].

Among them, MUC1 is directly regulated by HIF-1 in kidney cancer cells [START_REF] Aubert | MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor progression[END_REF].

MUC4

An anti-apoptotic role has been described for MUC4 in serum-free conditions [START_REF] Chaturvedi | MUC4 mucin potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins[END_REF][START_REF] Moniaux | Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells[END_REF] as well as following drug treatment with thymoquinone, an antioxidant and anti-tumoral compound found in plants [START_REF] Torres | Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies[END_REF], or with gemcitabine [START_REF] Bafna | Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin[END_REF][START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF]. MUC4 expression induces apoptosis via multiple intracellular mechanisms (Figure 3). It reduces mitochondrial cytochrome c release and activation of caspase-9 through phosphorylation of its partner HER2 and sequestration of pro-apoptotic Bad in the cytosol [START_REF] Bafna | Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin[END_REF][START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF]. Loss of MUC4 oncoprotein is accompanied by a blockage in the G1-early S phases [START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF][START_REF] Jonckheere | The Mucin MUC4 and Its Membrane Partner ErbB2 Regulate Biological Properties of Human CAPAN-2 Pancreatic Cancer Cells via Different Signalling Pathways[END_REF], an increased expression of the proapoptotic marker Bax and apoptotic mediator p53 as well as a decreased expression of the antiapoptotic Bcl XL suggesting a higher susceptibility to apoptosis [START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF]. The overexpression of rMuc4 induces chemoresistance to paclitaxel, doxorubicin and cisplatin. In this case, rMuc4 expression decreases PARP and caspase-9 cleavage and modulates apoptosis [START_REF] Hu | Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells[END_REF][START_REF] Komatsu | Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor[END_REF]. rMuc4 may also repress apoptosis via an ErbB2-dependent mechanism, in which rMuc4 potentiates the activation of ErbB2 by phosphorylation of the Y1248 leading to activation of the PI3K/Akt pathway, and via an ErbB2-independent mechanism that remains to be determined [START_REF] Jepson | Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways[END_REF][START_REF] Workman | 3rd, The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms[END_REF]. MUC4 overexpression in ovarian cancer cells also leads to increased CD133 + cell population. CD133 is a pentaspan transmembrane glycoprotein associated with chemoresistance, radio-resistance and poor prognosis and is commonly used as stem cell marker (see §7). Additionally, CD133 + cell population demonstrates significant resistance to drug-, TGFβand TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis compared with CD133 -cells [START_REF] El-Khattouti | Identification and analysis of CD133(+) melanoma stem-like cells conferring resistance to taxol: An insight into the mechanisms of their resistance and response[END_REF][START_REF] Li | CD133 expression in osteosarcoma and derivation of CD133(+) cells[END_REF] suggesting that CD133 triggers resistance to apoptosis in MUC4expressing cells via similar mechanisms.

Mucins and alteration of drug metabolism

In pancreatic cancer, chemoresistance has been attributed partly to the enhanced expression of multidrug resistance (MDR) genes (Figure 1C) including ATP-binding cassette transporter genes (ABCC)1, ABCC3, ABCC5 and ABCB1 that encode MDR related proteins (MRP)-1, MRP3, MRP5 and MDR1 proteins, respectively [START_REF] Nath | MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes[END_REF]. The proteins encoded by this gene family are ATP-dependent drug efflux pumps for xenobiotic compounds with broad substrate specificity [START_REF] Sharom | ABC multidrug transporters: structure, function and role in chemoresistance[END_REF]. Notably, cleaved MUC1-CT directly associates and activates the ABCC1 promoter and increases (i) ABCC1 protein level in MUC1-high pancreatic cancer cells and (ii) resistance to gemcitabine and etoposide chemotherapeutic drugs [START_REF] Nath | MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes[END_REF] (Figure 2).

One way to explain modifications of cell sensitivity to nucleoside analog such as gemcitabine or 5-FU is an alteration of the actors responsible for their metabolism and more particularly nucleoside transporters. We and others have described a major role for MUC4 in resistance to gemcitabine chemotherapy [START_REF] Bafna | Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin[END_REF][START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF][START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF] involving alteration of nucleotide metabolism. In that case, MUC4 mucin negatively regulates the hCNT1 transporter expression via the NF-B pathway, pointing out to MUC4 and hCNT1 as potential new targets to ameliorate the response of pancreatic tumors to gemcitabine treatment [START_REF] Skrypek | The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family[END_REF].

Cancer stem cells

The ability to relapse after therapy is frequently dependent on a small subset of the cell population within the tumor, called cancer stem cells (CSC) or side population (SP) (Figure 1D), characterized by an extensive self-renewing capacity [START_REF] Greaves | Clonal evolution in cancer[END_REF]. Some therapies including chemotherapy may provide strong selection for CSC survival and proliferation [START_REF] Gupta | Identification of selective inhibitors of cancer stem cells by high-throughput screening[END_REF].

Very recently, MUC1-CT was shown to upregulate expression of breast CSC marker

Aldehyde dehydrogenase 1A1 (ALDH1A1) via Erk1 and C/EBP by forming a transcriptional activating complex on the ALDH1A1 gene promoter [START_REF] Alam | MUC1-C oncoprotein activates ERK-->C/EBPbeta signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer cells[END_REF]. MUC1 was also shown to be expressed by CD34 + CD38 -acute myeloid leukemia (AML) cells which have been associated with leukemia stem cells (LSC) suggesting that MUC1 represents a potential target on the AML stem cell population [START_REF] Stroopinsky | MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells[END_REF].

In ovarian cancer, MUC4 overexpression leads to increased CD133-positive CSC [START_REF] Ponnusamy | MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells[END_REF] (Figure 3). Stem cell-like marker CD133 is also observed in a small subpopulation of pancreatic epithelial cells in the basal compartment in non-malignant pancreatic tissue specimens. This subpopulation also expresses MUC4 membrane-bound mucin [START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF]. MUC4 oncoprotein which is normally not expressed in the normal pancreas, is expressed at a high level in both the small CD133 + cell progenitor subpopulation as well as their differentiated CD133 -progenies.

Mimeault et al have suggested that MUC4 down-regulation can partially reverse the resistance of CD133+ initiating cells to the gemcitabine treatment [START_REF] Mimeault | MUC4 downregulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies[END_REF]. This is notably important since gemcitabine treatment of pancreatic tumor xenografts leads to enrichment of cell subpopulations expressing stem cell markers such as ALDH and CD24 as well as efflux pumps such as ABCB1 and ABCG2 [START_REF] Jimeno | A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development[END_REF][START_REF] Zhou | Persistence of side population cells with high drug efflux capacity in pancreatic cancer[END_REF]. MUC4 oncoprotein may thus represent a promising therapeutic strategy in that matter.

Epithelial-mesenchymal transition (EMT)

EMT is a physiological and pathological reversible biological process associated with loss of cellular polarity, decreased surface expression of epithelial markers (E-cadherin, cytokeratin-18, ZO-1) and increase mesenchymal markers expression (vimentin, N-cadherin, MMP-9, ZEB-1) (Figure 1E) [START_REF] Thiery | Epithelial-mesenchymal transitions in development and disease[END_REF][START_REF] Thiery | Complex networks orchestrate epithelial-mesenchymal transitions[END_REF]. EMT inducers include notably transcription factors, such as Snail, Slug, twist1/2, transforming growth factor (TGFß) pathway or miRNA [START_REF] Lamouille | Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs[END_REF][START_REF] Wendt | Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression[END_REF].

Many reports show that EMT is a major step toward metastatic tumor progression and contributes to drug resistance and acquisition or selection of stem/progenitor-like features and ultimately recurrence [START_REF] Ahmed | Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer[END_REF][START_REF] Lim | SNAI1-mediated epithelialmesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance[END_REF][START_REF] Voulgari | Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic[END_REF][START_REF] Yamada | Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer[END_REF].

MUC1 MUC4 and MUC16 are able to trigger the molecular process of EMT [START_REF] Comamala | Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells[END_REF][START_REF] Horn | ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumor cells induced by truncated MUC1[END_REF][START_REF] Roy | MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition[END_REF][START_REF] Ponnusamy | MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells[END_REF]. The mucin-induced EMT implies interaction with -catenin that leads to cell-cell junction disruption and invasiveness. Interestingly, MUC1-CT interacts with -catenin and translocates to the nucleus in order to upregulate EMT initiating genes. Moreover, MUC1-CT occupies and induces the ZEB1 promoter by a NF-B p65-dependent mechanism. In turn ZEB1 associates with MUC1-CT and contributes to suppress miR200c expression that promotes EMT [START_REF] Rajabi | MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition[END_REF]. In cRCC, MUC1-CT also occupies the Snail promoter, modulates the binding of β-catenin and trigger EMT [START_REF] Gnemmi | MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/beta-catenin pathway and interaction with SNAIL promoter[END_REF]. The cellular mechanisms underlying EMT related to MUC4 or MUC16 are not fully understood but might involve signaling pathway deregulation.

The relation between MUC4 and EMT is controversial since MUC4 was shown to suppress EMT in lung adenocarcinoma [START_REF] Gao | Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis[END_REF][START_REF] Jonckheere | Comment on: Functional MUC4 suppress epithelialmesenchymal transition in lung adenocarcinoma metastasis[END_REF] whereas MUC4 overexpression in ovarian cancer led to decreased expression of epithelial markers and occurrence of mesenchymal markers via an upregulation of Twist1, Twist2 and Snail transcription factors and FAK signaling pathway [START_REF] Ponnusamy | MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells[END_REF]. Collectively, these results suggest that MUC4 may regulate EMT in both ways depending on the cellular context. Complementary studies need to be carried out in order to elucidate these discrepancies regarding MUC4.

One may hypothesize that targeting EMT using MUC1 or MUC16 mucin as a therapeutic approach may be effective since mucins are involved in both chemoresistance and EMT that often lead to tumor recurrence. Recently, MUC1 siRNA was shown to inhibit both cell proliferation and EMT in urinary bladder cancer [START_REF] Fujii | ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression[END_REF].

Mucins and polymorphisms associated with chemosensitivity?

As genomic sequencing cost declines rapidly, the availability of pangenomic information promotes the era of pharmacogenomics and therefore personalized medicine. The genetic diversity between different population and ethnic backgrounds might explain a high degree of variability of drug response and adverse drug reactions [START_REF] Lee | The Emerging Era of Pharmacogenomics: Current Successes, Future Potential, and Challenges[END_REF]. Frequency differences of polymorphisms exist across different geographic regions for drug transporters or genes involved in drug metabolisms [START_REF] Ono | Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions[END_REF][START_REF] Sai | Ethnic differences in the metabolism, toxicology and efficacy of three anticancer drugs[END_REF].

Mucin single nucleotide polymorphisms (SNP), associated with various diseases including cancer, have been described [START_REF] Chang | MUC4 gene polymorphisms associate with endometriosis development and endometriosis-related infertility[END_REF][START_REF] Saeki | A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer[END_REF]. Moreover, the SNP distributions differ between subjects from different origins (Caucasian or Asian) [START_REF] Horimasu | Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels[END_REF]. Mucin genes also exhibit a high degree of polymorphisms in the VNTR domain [START_REF] Fowler | Polymorphism of the human muc genes[END_REF]. The variation of VNTR length leads to quantitative differences of the O-glycan content and alters biophysical properties of the glycoprotein. Among MUC associated with disease, gastric cancer patients harbor a higher proportion of short MUC1 allele compared to a control population [START_REF] Carvalho | MUC1 gene polymorphism and gastric cancer--an epidemiological study[END_REF]. Despite these data, no direct association between mucin polymorphism (SNP or VNTR) and sensitivity to chemotherapeutic drugs has been described so far.

Outlook to the future: Using mucins as a therapeutic target to sensitize cancer cells to chemotherapeutic drugs or as biomarkers of chemoresistance?

Since oncomucin expression in cancer cells is linked to a higher susceptibility to apoptosis, an increased expression of multidrug resistance markers, and stem cell characteristics, this could represent a valuable therapeutic strategy to decrease tumor resistance. Because of their high molecular weight and their high sugar content, extraction and purification of native mucins for therapy is notoriously difficult [START_REF] Davies | Gel-forming and cell-associated mucins: preparation for structural and functional studies[END_REF]. Therefore, native mucins were never used concomitantly with chemotherapeutic drugs. However, mucins expression or functionality was targeted in order to sensitize cancer cells to chemotherapeutic drugs.

Peptide inhibitors targeting MUC1-CT were shown to block its interaction with NF-B and to activate the induction of late apoptosis/necrosis in myeloma cells [START_REF] Yin | Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function[END_REF].

Silencing of MUC1 C-terminal subunit in HER2-overexpressing breast cancer cells or treatment with the penetrating peptide inhibitor, G0-203, reverses chemoresistance to trastuzumab, tamoxifen, taxol and doxorubicin (Figure 2) [START_REF] Kharbanda | Oncogenic MUC1-C Promotes Tamoxifen Resistance in Human Breast Cancer[END_REF][START_REF] Raina | Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells[END_REF][START_REF] Uchida | Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells[END_REF].

Silencing MUC1-CT is associated with (i) downregulation of HER2 phosphorylation and (ii) sensitivity to tamoxifen-induced growth inhibition and loss of clonogenic survival. HER2positive cancer cells that are intrinsically resistant to trastuzumab became sensitive when treated with an antagonist of the cleaved form of the MUC1 protein [START_REF] Fessler | MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells[END_REF]. In bladder cancer, MUC1 silencing also leads to reduction of tumor volume in vivo and suppresses EMT.

However, the impact on chemosensitivity remains to be proven in this case [START_REF] Fujii | ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression[END_REF].

Currently, phase 1 multi-center clinical trial testing G0-203 dose-escalation, safety, pharmacodynamic and pharmacokinetic in solid tumors and lymphomas is in progress (ClinicalTrials.gov identifier: NCT01279603). G0-203 also resulted in tumor regression independently of chemotherapy, in non-small cell lung cancer cells and acute myeloid leukemia [START_REF] Stroopinsky | MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells[END_REF][START_REF] Raina | Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells[END_REF].

Numerous studies are already targeting MUC1 as an immunotherapeutic approach [START_REF] Tang | Strategies used for MUC1 immunotherapy: preclinical studies[END_REF][START_REF] Tang | Strategies used for MUC1 immunotherapy: human clinical studies[END_REF][START_REF] Lakshminarayanan | Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine[END_REF][START_REF] Beatson | MUC1 immunotherapy[END_REF].

Mucins could also be used in modified vectors sensitizing the tumor to targeted chemotherapy. In OVCAR-3 ovarian cancer cells, a MUC1/let-7i chimera, combines MUC1 aptamer and let-7i miRNA, can specifically reverse chemoresistance to paclitaxel [START_REF] Liu | Reversal of paclitaxel resistance in epithelial ovarian carcinoma cells by a MUC1 aptamer-let-7i chimera[END_REF].

Similarly a MUC1/miR-29b chimera also reverses chemoresistance to paclitaxel [START_REF] Dai | The anti-chemoresistant effect and mechanism of MUC1 aptamer-miR-29b chimera in ovarian cancer[END_REF].

However, these effects on chemoresistance are independent of MUC1 structure since the MUC1 aptamer alone does not influence the induced apoptosis.

Therapy-predictive markers are factors that prospectively identify response or resistance to a specific treatment. They allow distinguishing patients with the same histological type of malignancy that respond very differently to a specific drug [START_REF] Duffy | Tumor markers in clinical practice: a review focusing on common solid cancers[END_REF]. In CRC, the presence of acellular mucin pools in the resected specimens of patients with a complete response to preoperative chemoradiation is frequently reported as a marker of treatment effect. However, several reports ruled out its prognostic significance [START_REF] De Campos-Lobato | Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation[END_REF][START_REF] Smith | Clinical significance of acellular mucin in rectal adenocarcinoma patients with a pathologic complete response to preoperative chemoradiation[END_REF][START_REF] Shia | Significance of acellular mucin pools in rectal carcinoma after neoadjuvant chemoradiotherapy[END_REF].

An ideal marker implicates non-invasive and rapid procedures of detection. Therefore, clinicians routinely use robust circulating markers in the blood or markers such as tumorassociated antigens. MUC1 (CA15-3) and MUC16 (CA125) tumor-associated antigens are commonly detected in patients' sera by standardized tests such as ELISA or immunohistochemistry [START_REF] Duffy | Tumor markers in clinical practice: a review focusing on common solid cancers[END_REF][START_REF] Budiu | Soluble MUC1 and serum MUC1-specific antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer[END_REF]. MUC1 and MUC16 are overexpressed in ovarian cancer [START_REF] Jonckheere | The membrane-bound mucins: From cell signalling to transcriptional regulation and expression in epithelial cancers[END_REF][START_REF] Aubert | Mucins in the uro-genital tract. Potential for therapeutic approaches using mucins[END_REF]. Budiu et al., showed that increased serum MUC1 level has a prognostic value for poor clinical response and reduced overall survival in platinum-resistant or platinumrefractory ovarian cancer whereas MUC16 was not associated with clinical response [START_REF] Budiu | Soluble MUC1 and serum MUC1-specific antibodies are potential prognostic biomarkers for platinum-resistant ovarian cancer[END_REF].

In a multivariable analysis, MUC1 protein and mRNA expression were independently predictive in a breast cancer cohort [START_REF] Sinn | Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer[END_REF]. CA15.3 level is also correlated with treatment response in patients undergoing chemotherapy for metastatic breast cancer [START_REF] Di Gioia | Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC)[END_REF]. Detection of (MUC1)-positive circulating tumor cells and MUC1 protein in the peripheral blood of patients with metastatic breast cancer is thus associated with higher progression-free survival (PFS) [START_REF] Cheng | MUC1-positive circulating tumor cells and MUC1 protein predict chemotherapeutic efficacy in the treatment of metastatic breast cancer[END_REF].

Conclusion

Over the past two decades, spectacular advances in targeted therapy led to improvement of treatment of a great numbers of cancer patients. These outstanding results are counterbalanced by the increased occurrence of acquired or intrinsic events of chemoresistance that limits long term success. Many evidence support the involvement of both membrane-bound and secreted mucins in diverse biological mechanims of resistance (physical barrier, apoptosis resistance, drug catabolism or exclusion, cell stemness, EMT). Understanding mechanisms of resistance involving mucins shall contribute to the development of next generation targeted therapy molecules. Alternatively, mucins will help in the prevention because of their potential as tumor biomarkers and orientate the therapeutic choice tree toward the potentially more successful therapy and more importantly avoid a more aggressive alternate therapy that is promised to failure.

  The steric hindrance of membrane-bound mucins is closely linked to the number and length of O-glycosidic chains worn by mucins. The benzyl-2-acetamido-2-deoxy-α-dgalactopyranoside (benzyl-α-GalNAc) is a reagent used to inhibit the synthesis of mucin Oglycosylation in cellular models. The inhibition of O-glycosylation in MUC1 expressing CAPAN-1 and HPAF-II pancreatic tumor cells resulted in significant 5-fluorouracile (5-FU)

Figure 1 :

 1 Figure 1: Mucins and chemoresistance in epithelial cells. (A) Secreted and membrane-

Figure 2 :

 2 Figure 2: MUC1 overexpression and associated cellular mechanisms of chemoresistance

Figure 3 :

 3 Figure 3: MUC4 overexpression and associated cellular mechanisms of chemoresistance

  Figure 1

  Figure 2

Table 1 : Mucins and drug chemoresistance in epithelial cancer cells

 1

	Mucin	Drug	Tumor type	Refs
		Membrane-bound mucins
	MUC1	5-FU/Methotrexate	CRC	[34, 35]
		5-FU	PDAC	[58, 60]
		Cisplatin	Ovarian	[52]
		Cisplatin	CRC	[67]
		Taxane/Platinum	Ovarian	[53]
		compound
		Trastuzumab/	Breast Cancer	[36]
		Paclitaxel/Doxorubicin/
		Cyclophosphamide
		Gemcitabine/Etoposide	PDAC	[90]
	MUC3	Methotrexate	CRC	[34]
	MUC4	5-FU	CRC	[34]
		Lapatinib/Trastuzumab	Breast Cancer	[39]
		Trastuzumab	Melanoma/Breast	[65]
			Cancer
		Cytarabine/Aracytin	PDAC	[42]
		Paclitaxel/Doxorubicin/	Melanoma	[44]
		Vinblastine/Rhodamine-
		123/2-deoxyglucose
		Bortezomib	PDAC	[43]
		Gemcitabine	PDAC	[40-42]
		Secreted mucins
	MUC5AC	5-FU/Methotrexate	CRC	[34, 35]
	MUC5B	5-FU/Methotrexate	CRC	[34, 35]
	MUC2	5-FU	CRC	[34]

Acknowledgements

We are grateful to Dr M. Perrais and Dr A. Vincent (Inserm UMR837, Lille) for their critical reading of the manuscript. This research was supported by SIRIC ONCOLille, Grant INCa-DGOS-Inserm 6041 and by a grant from la Ligue Nationale Contre le Cancer (Equipe Labellisée Ligue 2010, IVS). Isabelle Van Seuningen is the recipient of a "Contrat Hospitalier de Recherche Translationnelle"/CHRT 2010, AVIESAN.

Abbreviations