Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast

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.