Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes.

Abstract

One of the active intracellular pathways/networks in triple-negative breast carcinoma (TNBC) is that of the androgen receptor (AR). In this study, we examined AR and androgen-metabolising enzyme immunoreactivity in subcategories of TNBC to further elucidate the roles of androgenic pathways in TNBC. We utilised formalin-fixed paraffin-embedded breast cancer samples from ductal carcinoma in situ (DCIS) and invasive ductal carcinoma patient cohorts. We then used immunohistochemistry to classify these samples into basal-like and non-basal samples and to assess interactions between AR, androgen-metabolising enzymes and proliferation. To further substantiate our hypothesis and provide mechanistic insights, we also looked at the expression and regulation of these factors in publically available microarray data and in a panel of TNBC AR-positive cell lines. DCIS was associated with higher levels of AR and enzymes (p < 0.02), although a similar difference was not noticed in basal and non-basal samples. AR and enzymes were correlated in all states. In TNBC cell lines (MDA-MD-453, MFM-223 and SUM185-PE), we found that DHT treatment up-regulated 5αR1 and 17βHSD5 suggesting a mechanistic explanation for the correlations observed in the histological samples. Publicly available microarray data in TNBC cases suggested similar patterns to those observed in histological samples. In the majority of settings, including publically available microarray data, an inverse association between AR and proliferation was detected. These findings suggest that decreases in AR and androgen-metabolising enzymes may be involved in the increased biological aggressiveness in TNBC development.

• Authors: Keely M McNamara, Tomomi Yoda, Alif Meem Nurani, Yukiko Shibahara, Yasuhiro Miki, Lin Wang, Yasuhiro Nakamura, Koyu Suzuki, Yang Yang, Eriko Abe, Hisashi Hirakawa, Takashi Suzuki, Noriko Nemoto, Minoru Miyashita, Kentaro Tamaki, Takanori Ishida, Kristy A Brown, Noriaki Ohuchi, Hironobu Sasano
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 145 Issue 2 Pg. 281-93 (Jun 2014) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 24715382 (Publication Type: Comparative Study, Journal Article)

Chemical References

• AR protein, human
• Androgens
• Keratin-5
• Keratin-6
• Receptors, Androgen
• Dihydrotestosterone
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3
• Cholestenone 5 alpha-Reductase
• EGFR protein, human
• ErbB Receptors

Topics

• 3-Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Aldo-Keto Reductase Family 1 Member C3
• Androgens (metabolism)
• Carcinoma, Ductal, Breast (drug therapy, metabolism, pathology)
• Carcinoma, Intraductal, Noninfiltrating (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Cholestenone 5 alpha-Reductase (genetics, metabolism)
• Dihydrotestosterone (pharmacology)
• ErbB Receptors (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Keratin-5 (metabolism)
• Keratin-6 (metabolism)
• Receptors, Androgen (metabolism)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)