Novel Progesterone Receptor Target Gene Perilipin 2 Regulates Proliferation and Collagen Formation in Breast Cancer and Uterine Leiomyoma

Presentation Number: SUN-0042
Date of Presentation: June 22nd, 2014

Ping Yin*1, Antonia Navarro2, Molly B Moravek3, John S Coon V1, Matthew T Dyson3, Ranjani Sundar3 and Serdar Ekrem Bulun2
1Northwestern University, Chicago, IL, 2Northwestern Univ, Chicago, IL, 3Northwestern University

Abstract

Progesterone exerts an overall tumorigenic effect on both uterine leiomyoma (fibroid) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Previously, using an unbiased ChIP-sequencing technique, we uncovered perilipin 2 (ADRP/ADPH/PLIN2) as a novel PR target gene in T47D breast cancer cells and primary human uterine leiomyoma cells. RU486 treatment induced PLIN2 gene expression via the same DNA regulatory region in both cell types. PLIN2, an adipose differentiation-related protein, is ubiquitous in non-adipose lipid droplet-containing cells and plays important roles in lipid droplet formation and stabilization, but its loss is linked to the expression of fibrogenic genes in hepatic fibrosis. Moreover, in clear cell renal carcinoma, higher PLIN2 expression is associated with better cancer-specific survival and cancer-free survival. Until now, little is known about the roles of PLIN2 in the regulation of the growth of human uterine leiomyomas or breast cancers. In this study, we examined the impact of PLIN2 on the function of uterine fibroid cells and T47D cells by depleting its expression via small inference RNA (siRNA). We found that knockdown of PLIN2 with siRNA dramatically increased protein levels of proliferating cell nuclear antigen (a marker for cell proliferation) in both cell types. In T47D cells, PLIN2 knockdown also significantly stimulated the expression of fibrogenic genes including TIMP1 (2-fold), collagen 1a1 (1.5-fold), and collagen 1a2 (3-fold). Furthermore, we discovered that 75% of subjects’ leiomyoma tissues expressed lower mRNA levels of PLIN2 compared to the adjacent myometrial tissues. Our conclusions suggest that PLIN2 regulates cell proliferation and extracellular matrix formation in human T47D breast cancer cells and primary uterine leiomyoma cells, and we predict that PLIN2 plays an important role in mediating the therapeutic effects of RU486 in uterine leiomyomas and breast cancers.

 

Nothing to Disclose: PY, AN, MBM, JSC V, MTD, RS, SEB