PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy

Abstract

Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling-deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors-establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan-Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.

Keywords: PPARγ ligands; breast cancer; breast tumor microenvironment; peroxisome proliferator-activated receptor gamma; polyunsaturated fatty acids; thiazolidinediones.

Figure 1

Schematic illustration showing the role of PPARγ in breast cancer. Ligand-activated PPARγ induces gene expression changes, affecting breast cancer cells, tumor-associated macrophage (TAM), and cancer-associated fibroblast (CAF) behavior in in vitro experiments. Administration of PPARγ ligands alone or in combination with retinoid X receptor (RXR) agonists reduces tumor growth in in vivo models. PPARγ expression in clinical samples of breast cancer is positively associated with overall survival (OS), recurrence-free survival (RFS), post-progression survival (PPS), and distant metastasis-free survival (DMFS) (www.kmplot.com, accessed on 15 April 2021), representing a potentially favorable prognostic marker.