Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer
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Sweta Mishra1, Qin Tai1,7, Xiang Gu1, James Schmitz2, Ashley Poullard6, Roberto J. Fajardo2, Devalingam Mahalingam3, Xiaodong Chen4, Xueqiong Zhu5, Lu-Zhe Sun1,3
1Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA
2Department of Orthopedic Surgery, University of Texas Health Science Center, San Antonio, Texas, USA
3Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas, USA
4Dental School, University of Texas Health Science Center, San Antonio, Texas, USA
5Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
6Department of Medicine, Brown University, Providence, Rhode Island, USA
7Department of Vascular Surgery, The Second Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan, China
Lu-Zhe Sun, e-mail: SUNL@UTHSCSA.EDU
Keywords: prostate cancer, estrogen receptor, bone, osteoblastic, metastasis
Received: May 31, 2015 Accepted: October 22, 2015 Published: October 31, 2015
The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.
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