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Am J Cancer Res. 2015 Sep 15;5(10):3210-20. eCollection 2015.

Tumor suppressor SPOP mediates the proteasomal degradation of progesterone receptors (PRs) in breast cancer cells.

Author information

1
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University Shanghai, P. R. China.
2
Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, P. R. China.

Abstract

Progesterone induces proliferation of breast cancer cells and contributes to the development of breast cancer. The effects of progesterone are mediated by progesterone receptors (PRs). However, it is still not fully understood how the proliferative effects of PR is regulated in vivo. Increasing amount of evidence strongly suggests that dysregulation of ubiquitin-proteasome system is closely associated with cancer pathogenesis. Speckle-type POZ protein (SPOP) is an adaptor protein of the CUL3-based E3 ubiquitin ligase complexes. SPOP represents one of the highest loci for loss of heterozygosity (LOH) in breast cancer. SPOP downregulation contributes to breast cancer cell growth and invasion. In this study, we revealed PR as a bona fide substrate for SPOP. SPOP interacts with PR in vivo and targets PR for ubiquitin-dependent proteasomal degradation. Moreover, SPOP suppresses progesteroneinduced PR transactivation, S phase entry, and Erk1/2 activation. Our study revealed novel molecular mechanisms underlying the regulation of PR protein homeostasis in breast cancer cells, and provided insights in understanding the relationship between SPOP inactivation and the development of breast cancer.

KEYWORDS:

Breast cancer; SPOP; degradation; progesterone receptor; ubiquitination

PMID:
26693071
PMCID:
PMC4656742

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