title: Roles of the ER-α36-EGFR/HER2 positive regulatory loops in tamoxifen resistance.
abstract: Tamoxifen provided a successful treatment for ER-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to tamoxifen therapy. Extensive researches were conducted to understand the molecular mechanisms involved in tamoxifen resistance, and have revealed that multiple signaling molecules and pathways such as EGFR and HER2 are involved in tamoxifen resistance. Currently, the mechanisms by which tamoxifen sensitive breast cancer cells acquire these signaling pathways and develop tamoxifen resistance have not been elucidated. The identification of ER-α36, a variant of ER-α, that is able to mediate agonist activity of tamoxifen provided great insights into the underlying mechanisms of tamoxifen resistance. In this review, we will discuss the biological function and the possible underlying mechanisms of ER-α36 in tamoxifen resistance and specifically illustrate a novel cross-talk mechanism; positive regulatory loops between the ER-α36 and EGFR/HER2 in tamoxifen resistance. The function and the underlying mechanisms of ER-α36 in tamoxifen resistance of the breast cancer stem/progenitor cells will also be discussed. Finally, we will postulate a novel approach to restore tamoxifen sensitivity in tamoxifen resistant breast cancer cells.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE, USA. Electronic address: charlie.wang@shenogen.com.
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D066246:ErbB Receptors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C512478:EGFR protein, human
keywords: Breast cancer; EGFR; ER-α36; HER2; Tamoxifen resistance