title: Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer.
abstract: Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17β-estradiol (E2) has reemerged as a potential treatment option following exhaustive use of tamoxifen or aromatase inhibitors, although side effects have hindered its clinical usage. Protein kinase C alpha (PKCα) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEM) as an alternative to E2 for the treatment of tamoxifen-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCα-expressing, tamoxifen-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of tamoxifen-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of tamoxifen-resistant T47D:A18/PKCα and T47D:A18-TAM1 tumor models. T47D:A18/PKCα tumor regression was accompanied by translocation of estrogen receptor (ER) α to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. In addition, unlike E2 or tamoxifen, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Molloy
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Bethany E Perez
authors.initials: BE
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Teshome
authors.initials: T
authors.lastname: Gherezghiher
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Michalsen
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiong
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Hitisha
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
authors.forename: Philipp Y
authors.initials: PY
authors.lastname: Maximov
authors.affiliation: Department of Oncology, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois. dtonetti@uic.edu.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Tonetti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004967:Estrogens / Q000737:chemistry; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D013876:Thiophenes; C088015:benzothiophene; D013629:Tamoxifen