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.

Keywords: Androgen; aromatase; breast cancer; estrogen; invasive lobular carcinoma.

Fig 1

Representative illustrations of androgen receptor (AR), 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5), and 5α-Reductase type 1 (5αRed1) immunohistochemistry in AR+/17βHSD5+/5αRed1+ (b–d) and AR−/17βHSD5−/5αRed1− (f–h) invasive lobular carcinoma cases. Hematoxylin–eosin staining (a,e). Androgen receptor was immunolocalized in the nuclei of carcinoma cells (b,f), and 17βHSD5 (c,g) and 5αRed1 (d,h) immunolocalized in the cytoplasm of carcinoma cells. Scale bar = 100 μm.

Fig 2

Tumor size was inversely correlated with the status of androgenic enzymes in androgen receptor-positive invasive lobular carcinoma cases. Data of tumor size were available from a subset of breast cancer patients treated at Tohoku University Hospital or Tohoku Kosai Hospital. *P < 0.05. 17βHSD5, 17β-hydroxysteroid dehydrogenase type 5; 5αRed1, 5α-reductase type 1.

Fig 3

Absence of intratumoral androgenic enzymes was significantly correlated with adverse clinical outcome in breast cancer patients. Clinical information regarding overall survival (OS) and disease-free survival (DFS) was available for cases from Tohoku University Hospital and Tohoku Kosai Hospital. Only patients with survival data greater than 5 years (surgical date before 2008) were included in this study. The OS (a) and DFS (b) of these patients were analyzed according to the status of intratumoral androgenic enzymes 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1) using the Kaplan–Meier method (n = 72).

Fig 4

Status of 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) immunoreactivity was significantly higher in invasive lobular carcinoma (ILC) than in invasive ductal carcinoma (IDC) and inversely associated with tumor size in ILC cases. (a) 17βHSD2 mRNA expression in four IDC and four ILC cases was analyzed using RT² quantitative PCR. (b) Representive illustrations of 17βHSD2 positive (left) and negative (right) cases in IDC (top) and ILC (bottom). 17βHSD2 was localized in the cytoplasm of carcinoma cells. Scale bar = 100 μm. (c) 17βHSD2 immunoreactivity in ILC and IDC specimens. (d) Correlation between 17βHSD2 and androgenic enzymes in androgen receptor-positive ILC cases. (e) Tumor size was inversely correlated with 17βHSD2 expression. Data of tumor size were available in a subset of breast cancer patients treated at Tohoku University Hospital or Tohoku Kosai Hospital. **P < 0.01. 17βHSD5, 17β-hydroxysteroid dehydrogenase type 5; 5αRed1, 5α-reductase type 1.