Peroxisome Proliferator-Activated Receptor as a Therapeutic Target in Human Breast Cancer

Hall Jm Robinson Ml

doi:10.4172/2157-7536.1000155

Abstract

Objective: Peroxisome proliferator-activated receptor γ (PPARγ) is aberrantly expressed in most breast tumors, suggesting the potential of agents that target this receptor in treatment and chemoprevention of breast cancer. However, whether PPARγ leads to the promotion or reduction of tumor formation has remained controversial and is further complicated by the ability of its available thiazolidinedione (TZD) ligands to activate another PPAR subtype, PPARδ. Method: To examine the role of each receptor in breast cancer biology, we performed a systematic evaluation of PPARγ and PPARδ agonists on the growth of human estrogen receptor (ER)-positive and -negative breast cancer cells. Results: In this manner we found that TZD-activated PPARγ was highly effective in suppressing the proliferation of estrogen-dependent cancer cells. Activated PPARδ, however, displayed growth-enhancing effects independent of estradiol and regardless of the ER status of the cells. Strikingly, in ER-negative cancer cells expressing a favorable PPARδ/γ ratio, TZDs promoted growth in a PPAR γ-independent manner by direct activation of PPARδ. A screen for ligands with increased receptor selectivity compared to TZDs revealed that GW7845 functioned as a full agonist of PPARγ, yet this agent lacked the ability to activate PPARδ and elicit its associated mitogenic effects. Conclusion: These studies indicate that selective PPAR γ modulators (SPPARγMs) that lack agonist activity on PPARδ may be clinically useful in future cancer treatment and chemoprevention.

Highlights

ResultsIn this manner we found that TZD-activated Peroxisome proliferator-activated receptor γ (PPARγ) was highly effective in suppressing the proliferation of estrogen-dependent cancer cells
Breast cancer is currently the most prevalent malignancy among women in industrialized countries, and one in eight women living in the United States will develop the disease at some point in her lifetime
The aberrant over-representation of PPARs in breast cancers, together with their suspect roles in tumor biology, prompted us to investigate the relationship between Peroxisome proliferator-activated receptor γ (PPARγ) and δ expression, receptor activity, and associated impact on cancer biology

Summary

Results

It has been well established that gene expression patterns have the ability to define clinically relevant risk factors in disease prognosis [28,29,30]. This was reflected in our gene validation analysis, as the expression of the estrogen responsive progesterone receptor (PR), pS2 and ID3 mRNAs remained unchanged with the addition of PPARγ agonists (Figure 2B) These data indicate that PPARγ agonists can oppose estradiol in modulating expression of key regulators of growth in human breast cancer cells, an activity consistent with the suppressive effects of these agents on estrogen-dependent proliferation. The effect of GW7845 on estrogen-stimulated growth of two ERα/PPARγ-positive breast cancer cell lines was examined (Figure 5A) Both the MCF-7 and ZR-75 cells displayed a mitogenic response to estradiol that was completely attenuated with coadministration of GW7845. The PPAR subtype-selective activities of GW7845 are reflected in both its receptor pharmacology (Figure 4) and biology in breast cancer cells (Figure 5)

Conclusion

Introduction

Discussion