title: Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast.
abstract: Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen-responsive environment, the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (P < 0.0001) and intratumoral 17βHSD2 was inversely correlated with tumor size in ILC (P = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen-producing enzymes could play pivotal protective roles in AR-enriched ILC cases.
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yoda
authors.forename: Keely May
authors.initials: KM
authors.lastname: McNamara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Mayu
authors.initials: M
authors.lastname: Takagi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Rai
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Ohi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Sagara
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tamaki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hirakawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Ishida
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ohuchi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D047368:Tumor Burden
chemical_list: D000728:Androgens; D014408:Biomarkers, Tumor; D004960:Estradiol Dehydrogenases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: Androgen; aromatase; breast cancer; estrogen; invasive lobular carcinoma