title: MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ERα expression and AKT activation.
abstract: Tamoxifen resistance presents a prominent clinical challenge in endocrine therapy for hormone sensitive breast cancer. However, the underlying mechanisms that contribute to tamoxifen resistance are not fully understood. In this study, we established a tamoxifen resistant MCF-7 cell line (MCF-7-Tam-R) by continuously incubating MCF-7 cells with 4-OH-tamoxifen. We found that melanoma cell adhesion molecule (MCAM/CD146), a unique epithelial-to-mesenchymal transition (EMT) inducer, was significantly up-regulated at both mRNA and protein levels in MCF-7-Tam-R cells compared to parental MCF-7 cells. Mechanistic research demonstrated that MCAM promotes tamoxifen resistance by transcriptionally suppressing ERα expression and activating the AKT pathway, followed by induction of EMT. Elevated MCAM expression was inversely correlated with recurrence-free and distant metastasis-free survival in a cohort of 4142 patients with breast cancer derived from a public database, particularly in the subgroup only treated with tamoxifen. These results demonstrate a novel function of MCAM in conferring tamoxifen resistance in breast cancer. Targeting MCAM might be a promising therapeutic strategy to overcome tamoxifen resistance in breast cancer patients.
authors.affiliation: The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China; ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China; Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Yuan-Ke
authors.initials: YK
authors.lastname: Liang
authors.affiliation: ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China; Department of Breast Medical Oncology, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China.
authors.forename: De
authors.lastname: Zeng
authors.affiliation: The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China; ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Ying-Sheng
authors.initials: YS
authors.lastname: Xiao
authors.affiliation: The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China; ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Yan-Xiu
authors.initials: YX
authors.lastname: Ouyang
authors.affiliation: ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Yao-Chen
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou, China.
authors.forename: Hao-Yu
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Pathology, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Wei
authors.affiliation: The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China; ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China.
authors.forename: Yong-Qu
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address: f.a.e.kruyt@umcg.nl.
authors.forename: Frank A E
authors.initials: FA
authors.lastname: Kruyt
authors.affiliation: The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, China; ChangJiang Scholar's Laboratory of Shantou University Medical College, 22 Xinling Road, Shantou, China. Electronic address: guoj_zhang@yahoo.com.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D016208:Databases, Factual; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051929:CD146 Antigen; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C497902:MCAM protein, human; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT pathway; Breast cancer; ERα; MCAM/CD146; Tamoxifen resistance