Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma

• Published in: Breast cancer research and treatment Vol. 166; no. 3; pp. 709 - 723
• Main Authors: Kikuchi, Kyoko, McNamara, Keely May, Miki, Yasuhiro, Moon, Ju-Yeon, Choi, Man Ho, Omata, Fumiya, Sakurai, Minako, Onodera, Yoshiaki, Rai, Yoshiaki, Ohi, Yasuyo, Sagara, Yasuaki, Miyashita, Minoru, Ishida, Takanori, Ohuchi, Noriaki, Sasano, Hironobu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2017; Springer; Springer Nature B.V
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; Actins - genetics; Analysis; Androgens; Androgens - genetics; Androgens - metabolism; Angiogenesis; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer metastasis; Cancer research; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma; Cell culture; Cell Line, Tumor; Cell Proliferation - genetics; Coculture Techniques; Cytokines; Enzymes; Estradiol Dehydrogenases - genetics; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; Evaluation; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor - genetics; Humans; Immunohistochemistry; Interleukin 6; Interleukin-6 - genetics; Medical schools; Medicine; Medicine & Public Health; Metabolism; Metastases; Oncology; Paracrine signalling; Phenols (Class of compounds); Polymerase chain reaction; Preclinical Study; Receptors, Androgen - genetics; Stat3 protein; Stromal cells; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Western blotting; Cancer-associated fibroblasts (CAFs); Breast cancer; Triple-negative breast cancer (TNBC); Microenvironment; Androgen
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4464-5

Purpose The tumor microenvironment plays pivotal roles in promotion of many malignancies. Cancer-associated fibroblasts (CAFs) have been well-known to promote proliferation, angiogenesis, and metastasis but mechanistic understanding of tumor–stroma interactions is not yet complete. Recently, estrogen synthetic enzymes were reported to be upregulated by co-culture with stromal cells in ER positive breast carcinoma (BC) but effects of co-culture on androgen metabolism have not been extensively examined. Therefore, we evaluated roles of CAFs on androgen metabolism in ER-negative AR-positive BC through co-culture with CAFs. Methods C oncentrations of steroid hormone in supernatant of co-culture of MDA-MB-453 and primary CAFs were measured using GC–MS. Cytokines derived from CAFs were determined using Cytokine Array. Expressions of androgen synthetic enzymes were confirmed using RT-PCR and Western blotting. Correlations between CAFs and androgen synthetic enzymes were analyzed using triple-negative BC (TNBC) patient tissues by immunohistochemistry. Results CAFs were demonstrated to increase expressions and activities of 17βHSD2, 17βHSD5, and 5α-Reductase1. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17βHSD2, 17βHSD5, and 5α-Reductase1 expression. Underlying mechanisms of IL-6 paracrine regulation of 17βHSD2 and 17βHSD5 could be partially dependent on phosphorylated STAT3, while phosphorylated ERK could be involved in HGF-mediated 5α-Reductase1 induction. α-SMA status was also demonstrated to be significantly correlated with 17βHSD2 and 17βHSD5 status in TNBC tissues, especially AR-positive cases. Conclusions Results of our present study suggest that both IL-6 and HGF derived from CAFs could contribute to the intratumoral androgen metabolism in ER-negative BC patients.