title: The steroid receptor coactivator-3 is required for developing neuroendocrine tumor in the mouse prostate.
abstract: Neuroendocrine tumor cells (NETCs) are commonly observed in prostate cancer. Their presence is associated with castration resistance, metastasis and poor prognosis. Cellular and molecular mechanisms for NETC initiation and growth are unknown. TRAMP mice develop heterogeneous adenocarcinomas induced by expression of the SV40-T/t oncogene in prostate epithelial cells. Here, we demonstrate prostate tumors in TRAMP mice with a mixed genetic background are characterized mostly by atypical hyperplasia (AH) containing steroid receptor coactiator-3-positive, androgen receptor-positive and synaptophysin-negative (SRC-3+/AR+/Syp-) cells. Few SRC-3+/AR-/Syp+ NETCs are present in their prostates. We generated TRAMP mice in which SRC-3 was specifically ablated in AR+/Syp- prostatic epithelial cells (termed PE3KOT mice). In these animals, we observed a substantial reduction in SRC-3-/AR+/Syp- AH tumor growth. There was a corresponding increase in SRC-3-/AR+/Syp- phyllodes lesions, suggesting SRC-3 knockout can convert aggressive AH tumors with mostly epithelial tumor cells into less aggressive phyllodes lesions with mostly stromal tissue. Surprisingly, PE3KOT mice developed many more SRC-3+/AR-/Syp+ NETCs versus control TRAMP mice, indicating SRC-3 expression was retained in NETCs. In contrast, TRAMP mice with global SRC-3 knockout did not develop any NETC, indicating SRC-3 is required for developing NETC. Analysis of cell-differentiating markers revealed that these NETCs might not be derived from the mature AR-/Syp+ neuroendocrine cells or the AR+/Syp- luminal epithelial tumor cells. Instead, these NETCs might originate from the SV40-T/t-transformed intermediate/progenitor epithelial cells. In summary, SRC-3 is required for both AR+/Syp- AH tumor growth and AR-/Syp+ NETC development, suggesting SRC-3 is a target for inhibiting aggressive prostate cancer containing NETCs.
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; ; 2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA;
authors.forename: Jean Ching-Yi
authors.initials: JC
authors.lastname: Tien
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Lan
authors.initials: L
authors.lastname: Liao
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; ; 2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA;
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; ; 2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA;
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
authors.forename: Dong-Kee
authors.initials: DK
authors.lastname: Lee
authors.affiliation: 2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA;
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; ; 2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA; ; 3. Insitute for Cancer Medicine, Luzhou Medical College, Luzhou, Sichuan 646000, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D006652:Histological Techniques; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018358:Neuroendocrine Tumors / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D016708:Synaptophysin; C569015:Syp protein, mouse; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3
keywords: SRC-3/NCOA3; carcinogenesis; coactivator; neuroendocrine cell; prostate epithelium; transgenic mouse model.