title: Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.
abstract: Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.
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: Tatsuyuki
authors.initials: T
authors.lastname: Gohno
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: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D008954:Models, Biological; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D011960:Receptors, Estrogen; D013256:Steroids; D004958:Estradiol; D001141:Aromatase