Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells

作者：Zaytseva Yekaterina Y; Wang Xin; Southard R Chase; Wallis Natalie K; Kilgore Michael W^*

来源：Molecular Cancer, 2008, 7: 90.

DOI：10.1186/1476-4598-7-90

Background: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPAR gamma has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPAR gamma signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies are inconsistent and suggest that endogenous activation of PPAR gamma plays a much more complex role in initiation and progression of cancer than previously thought.
Results: We have previously demonstrated that an increase in expression of PPAR gamma 1 in MCF-7 breast cancer cells is driven by a tumor-specific promoter. Myc-associated zinc finger protein (MAZ) was identified as a transcriptional mediator of PPAR gamma 1 expression in these cells. In this study, using RNA interference (RNAi) to inhibit PPAR gamma 1 expression directly or via down-regulation of MAZ, we report for the first time that a decrease in PPAR gamma 1 expression results in reduced cellular proliferation in MCF-7 breast cancer cells. Furthermore, we demonstrate that these changes in proliferation are associated with a significant decrease in cell transition from G(1) to the S phase. Using a dominant-negative mutant of PPAR gamma 1, Delta 462, we confirmed that PPAR gamma 1 acts as a pro-survival factor and showed that this phenomenon is not limited to MCF-7 cells. Finally, we demonstrate that down-regulation of PPAR gamma 1 expression leads to an induction of apoptosis in MCF-7 cells, confirmed by analyzing Bcl-2 expression and PARP-1 cleavage.
Conclusion: Thus, these findings suggest that an increase in PPAR gamma 1 signaling observed in breast cancer contributes to an imbalance between proliferation and apoptosis, and may be an important hallmark of breast tumorigenesis. The results presented here also warrant further investigation regarding the use of PPAR gamma ligands in patients who are predisposed or already diagnosed with breast cancer.

• 出版日期2008-12-5