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 2024-01-20T00:01:47Z 2024-01-20T00:01:47Z 2021-09-03 2017-12 0167-6806 https://pubs.kist.re.kr/handle/201004/121982 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. Concentrations 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. CAFs were demonstrated to increase expressions and activities of 17 beta HSD2, 17 beta HSD5, and 5 alpha-Reductase1. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17 beta HSD2, 17 beta HSD5, and 5 alpha-Reductase1 expression. Underlying mechanisms of IL-6 paracrine regulation of 17 beta HSD2 and 17 beta HSD5 could be partially dependent on phosphorylated STAT3, while phosphorylated ERK could be involved in HGF-mediated 5 alpha-Reductase1 induction. alpha-SMA status was also demonstrated to be significantly correlated with 17 beta HSD2 and 17 beta HSD5 status in TNBC tissues, especially AR-positive cases. 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. English SPRINGER STROMAL FIBROBLASTS CELL-PROLIFERATION GENE-EXPRESSION ACTIVATION GROWTH STAT3 INTERLEUKIN-6 AROMATASE SUBTYPES MICROENVIRONMENT Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma Article 10.1007/s10549-017-4464-5 1 BREAST CANCER RESEARCH AND TREATMENT, v.166, no.3, pp.709 - 723 BREAST CANCER RESEARCH AND TREATMENT 166 3 709 723 scie scopus 000415126700006 2-s2.0-85027839481 Oncology Oncology Article STROMAL FIBROBLASTS CELL-PROLIFERATION GENE-EXPRESSION ACTIVATION GROWTH STAT3 INTERLEUKIN-6 AROMATASE SUBTYPES MICROENVIRONMENT Breast cancer Triple-negative breast cancer (TNBC) Microenvironment Cancer-associated fibroblasts (CAFs) Androgen