title: Disruption of the ER-α36-EGFR/HER2 positive regulatory loops restores tamoxifen sensitivity in tamoxifen resistance breast cancer cells.
abstract: Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, most breast tumors develop tamoxifen resistance and are eventually refractory to tamoxifen therapy. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-α36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-α36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-α36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-α36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-α36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-α36-EGFR/HER2 loops.
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Zhang
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America.
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human