Kyoko Kikuchi1, Keely May McNamara2, Yasuhiro Miki3, Ju-Yeon Moon4, Man Ho Choi4, Fumiya Omata1, Minako Sakurai1, Yoshiaki Onodera1, Yoshiaki Rai5, Yasuyo Ohi5, Yasuaki Sagara5, Minoru Miyashita6, Takanori Ishida6, Noriaki Ohuchi6, Hironobu Sasano1. 1. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai-shi, Miyagi, 980-8575, Japan. 2. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai-shi, Miyagi, 980-8575, Japan. kmcnamara@patholo2.med.tohoku.ac.jp. 3. Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDeS), Tohoku University, 2-1, Seiryo-machi, Aoba-Ku, Sendai-shi, Miyagi, 980-8575, Japan. 4. Molecular Recognition Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seoul, 02792, Korea. 5. Sagara Hospital, Social Medical Corporation Hakuaikai, Kagoshima, Japan. 6. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai-shi, Miyagi, 980-8575, Japan.
Abstract
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: 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. 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.
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: 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. 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.
Entities:
Keywords:
Androgen; Breast cancer; Cancer-associated fibroblasts (CAFs); Microenvironment; Triple-negative breast cancer (TNBC)
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