title: Downregulation of ER-α36 expression sensitizes HER2 overexpressing breast cancer cells to tamoxifen.
abstract: Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, HER2 overexpressing breast cancer cells respond poorly to tamoxifen therapy presumably by pass. 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, NE, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Breast and Thyroid surgery, Shandong Provincial Hospital Affiliated to Shandong University Jinan 250021, Shandong, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School Omaha, NE, USA.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Zhang
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School Omaha, NE, USA.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School Omaha, NE, USA.
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University Jinan 250012, Shandong, China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University Jinan 250012, Shandong, China.
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
keywords: EGFR; ER-α36; HER2; breast cancer; tamoxifen resistance