The steroid receptor coactivator-3 is required for developing neuroendocrine tumor in the mouse prostate

Jean Ching Yi Tien, Lan Liao, Yonghong Liu, Zhaoliang Liu, Dong Kee Lee, Fen Wang, Jianming Xu

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1116-1127
Number of pages12
JournalInternational Journal of Biological Sciences
Volume10
Issue number10
DOIs
StatePublished - Oct 2 2014
Externally publishedYes

Keywords

  • Carcinogenesis
  • Coactivator
  • Neuroendocrine cell
  • Prostate epithelium
  • SRC-3/NCOA3
  • Transgenic mouse model

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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