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.

PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer

“…PPAR-γ is frequently expressed in various cancer cells, including breast, lung, colon, lips, kidney, pancreatic and thyroid [ 32 ]. Several studies have revealed that PPAR-γ activation by its agonists imposes cell cycle arrest [ 33 ], apoptosis [ 34 ], angiogenesis [ 35 ], inhibition [ 36 ], and redifferentiation [ 37 ], which are the key molecular processes associated with the prevention of tumor growth and progression. The expression of angiogenesis-related proteins such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 as well as inflammatory mediators in the tumor microenvironment are all inhibited by PPAR-γ activation [ 38 ].…”

Nutraceuticals in the Mediterranean Diet: Potential Avenues for Breast Cancer Treatment

“…Upon ligand binding, PPARs can modulate target gene expression by binding to the peroxisome proliferator responsive element (PPRE) in target genes [ 54 ]. Specifically, PPARγ activation inhibits tumor cell growth in vitro and in vivo model systems, suggesting the potential role of this receptor for cancer therapy [ 55 , 56 , 57 , 58 ]. Retinoids alone or in combination with PPARγ agonists are cell differentiation agents, which play a fundamental role in controlling cell proliferation and metabolism [ 59 , 60 ].…”

Phase separation-mediated biomolecular condensates and their relationship to tumor

“…PPARγ activation occurs through natural or synthetic ligands like ω-3 polyunsaturated fatty acids (PUFA) and thiazolidinediones (TZD). Upon activation, PPARγ forms a heterodimer with RXR, translocates to the nucleus, and binds to the PPRE of PPARγ target genes, initiating gene transcription and participating in the regulation of multiple gene expressions [ 142 ]. Studies specifically in breast cancer have revealed the significant role of ligand-bound PPARγ in inhibiting the growth, metastasis, and invasion of breast cancer cells, impacting cell cycle regulation, and influencing both endogenous and exogenous apoptosis across various breast cancer subtypes, including ER + /PR + , ER-/PR-, HER + , and triple-negative breast cancer cells [ 143 ].…”