title: Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism.
abstract: Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-Androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3β-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3β-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen metabolite-induced ER activation and growth mechanisms. Androgen metabolite-dependent growth of breast cancer cells may therefore play a role in AI-resistance.
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. hanamura@shinshu-u.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Hanamura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Niwa
authors.forename: Sayo
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Konno
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Gohno
authors.forename: Chika
authors.initials: C
authors.lastname: Tazawa
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kurosumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takei
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ito
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hayashi
mesh_terms: D000728:Androgens / Q000378:metabolism*; D015113:Androstane-3,17-diol / Q000378:metabolism / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077289:Letrozole; D061986:MCF-7 Cells / Q000187:drug effects; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D013251:Steroid Isomerases / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D000728:Androgens; D047072:Aromatase Inhibitors; D009097:Multienzyme Complexes; D009570:Nitriles; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D014230:Triazoles; D013196:Dihydrotestosterone; D049452:Green Fluorescent Proteins; D015113:Androstane-3,17-diol; D013739:Testosterone; D000077289:Letrozole; D011375:Progesterone Reductase; D013251:Steroid Isomerases