title: Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer.
abstract: Tamoxifen resistance of estrogen receptor-positive (ER+) breast cancer cells has been linked in part to activation of receptor tyrosine kinases, such as HER2, and the PI3K-AKT pathway. Mucin 1 (MUC1) is aberrantly overexpressed in about 90% of human breast cancers, and the oncogenic MUC1-C subunit is associated with ERα. The present studies using HER2 overexpressing BT-474 breast cancer cells, which are constitutively resistant to tamoxifen, demonstrate that silencing MUC1-C is associated with (i) downregulation of p-HER2 and (ii) sensitivity to tamoxifen-induced growth inhibition and loss of clonogenic survival. In contrast, overexpression of MUC1-C in tamoxifen-sensitive MCF-7 breast cancer cells resulted in upregulation of p-AKT and tamoxifen resistance. We show that MUC1-C forms complexes with ERα on the estrogen-responsive promoter of Rab31 and that MUC1-C blocks tamoxifen-induced decreases in ERα occupancy. MUC1-C also attenuated tamoxifen-induced decreases in (i) recruitment of the coactivator CREB binding protein, (ii) Rab31 promoter activation, and (iii) Rab31 mRNA and protein levels. The importance of MUC1-C is further supported by the demonstration that targeting MUC1-C with the cell-penetrating peptide inhibitor, GO-203, sensitized tamoxifen-resistant cells to tamoxifen treatment. Moreover, we show that targeting MUC1-C in combination with tamoxifen is highly synergistic in the treatment of tamoxifen-resistant breast cancer cells. Combined, these findings indicate that MUC1-C contributes to tamoxifen resistance.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Akriti
authors.initials: A
authors.lastname: Kharbanda
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Caining
authors.initials: C
authors.lastname: Jin
authors.forename: Deepak
authors.initials: D
authors.lastname: Raina
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D018396:Mucin-1 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D018396:Mucin-1; D009363:Neoplasm Proteins; D010455:Peptides; D021122:Protein Subunits; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D020691:rab GTP-Binding Proteins; C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C506487:ESR1 protein, human; C060192:MUC1 protein, human; C484190:RAB31 protein, human
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