Androgen receptor decreases CMYC and KRAS expression by upregulating let-7a expression in ER-, PR-, AR+ breast cancer

Lyu,Shuhua; Yu,Qi; Ying,Guoguang; Wang,Shuling; Wang,Yahong; Zhang,Jing; Niu,Yun

doi:10.3892/ijo.2013.2151

Androgen receptor decreases CMYC and KRAS expression by upregulating let-7a expression in ER-, PR-, AR+ breast cancer

Authors:
- Shuhua Lyu
- Qi Yu
- Guoguang Ying
- Shuling Wang
- Yahong Wang
- Jing Zhang
- Yun Niu
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Affiliations: Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education and Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China, Department of Oncology, Jinghai Hospital, Tianjin 301600, P.R. China, Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
Published online on: October 25, 2013 https://doi.org/10.3892/ijo.2013.2151
Pages: 229-237

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Abstract

It is generally known that the decision to use anti-estrogen therapy is based on the expression of estrogen and progesterone receptors in breast cancers. Recent studies have shown that androgen receptor (AR) is frequently expressed in ER-, PR- breast cancer and plays an important role in the prognosis of breast cancer patients. Furthermore, AR can increase the global expression of microRNAs, post-transcriptional gene regulators that play a crucial role in the initiation and progression of breast cancer. In this study, we investigated the functions and relations of AR, related miRNAs and target proteins in ER-, PR-, AR+ breast cancer. The results showed that androgen-induced AR activating signal directly upregulates let-7a expression, downregulates CMYC and KRAS protein expression, and inhibits cell proliferation in ER-, PR-, AR+ breast cancer cells. Overexpression of let-7a inhibits cell proliferation and downregulates CMYC and KRAS protein expression, whereas inhibition of let-7a expression by specific antisense oligonucleotides increases cell growth and upregulates CMYC and KRAS protein expression. We performed in situ hybridization for let-7a and immunohistochemical staining for CMYC and KRAS using sequential sections obtained from surgically-resected breast cancer tissues and observed an inverse correlation between the staining pattern of let-7a and its target proteins. Androgen-induced AR activating signal upregulates let-7a that targets CMYC and KRAS and contributes to ER-, PR-, AR+ breast cancer pathogenesis. Elucidation of this pathway will help develop new therapies.

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