title: Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells.
abstract: Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 micromol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10(-7) mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Delta16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER(alpha) mRNA and protein without an effect on ER(beta) levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE(2)e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER(alpha) levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
authors.affiliation: Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Mariam
authors.initials: M
authors.lastname: Al-Dhaheri
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Clement
authors.initials: C
authors.lastname: Ip
authors.forename: Frank E
authors.initials: FE
authors.lastname: Jones
authors.forename: Brian G
authors.initials: BG
authors.lastname: Rowan
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D016566:Organoselenium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C489427:MYC protein, human; D016566:Organoselenium Compounds; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; C016601:afimoxifene; C008493:methylselenic acid