Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor negative breast carcinoma
- Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor negative breast carcinoma
- 최만호; Kyoko Kikuchi; Keely May McNamara; Yasuhiro Miki; Ju-Yeon Moon; Fumiya Omata; Minako Sakurai; Yoshiaki Onodera; Yoshiaki Rai; Yasuyo Ohi; Yasuaki Sagara; Minoru Miyashita; Takanori Ishida; Noriaki Ohuchi; Hironobu Sasano
- Breast Cancer; Steroid
- Issue Date
- Breast cancer research and treatment
- VOL 166, NO 3-723
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 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.
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.
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