Stromal adipocyte PPARγ protects against breast tumorigenesis

Abstract

Peroxisome proliferator-activated receptor (PPAR)γ regulates the expression of genes essential for fat storage, primarily through its activity in adipocytes. It also has a role in carcinogenesis. PPARγ normally stops the in vivo progression of 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumours as revealed with PPARγ haploinsufficient mice. Since many cell types associated with the mammary gland express PPARγ, each with unique signal patterns, this study aimed to define which tissues are required for PPARγ-dependent antitumour effects. Accordingly, adipocyte-specific PPARγ knockout (PPARγ-A KO) mice and their wild-type (PPARγ-WT) controls were generated, and treated with DMBA for 6 weeks to initiate breast tumorigenesis. On week 7, mice were randomized to continue on normal chow diet or one supplemented with rosiglitazone (ROSI), and followed for 25 weeks for tumour outcomes. In PPARγ-A KO versus PPARγ-WT mice, malignant mammary tumour incidence was significantly higher and mammary tumour latency was decreased. DMBA + ROSI treatment reduced average mammary tumour volumes by 50%. Gene expression analyses of mammary glands by quantitative real-time polymerase chain reaction and immunofluorescence indicated that untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes. Compared with PPARγ-WT mice, serum leptin levels in PPARγ-A KOs were also significantly higher throughout the study. Together, these data are the first to suggest that in vivo PPARγ expression in mammary stromal adipocytes attenuates breast tumorigenesis through BRCA1 upregulation and decreased leptin secretion. This study supports a protective effect of activating PPARγ as a novel chemopreventive therapy for breast cancer.

Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ

“…With regard to mammary biology, previous studies have mainly focused on the role of PPARγ as a mammary tumor suppressor (37)(38)(39)(40). Interestingly, conditional knockout of PPARγ in mammary epithelium did not affect normal mammary development (41).…”

DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers

“…This nuclear receptor acts as a tumor suppressor and the loss of its expression has been shown to contribute to the creation of a protumorigenic environment in breast tissue [34,35]. Therefore, the downregulation of this tumor suppressor could, together with impaired function of BRCA1, contribute to the increased susceptibility to breast cancer for carriers of specific BRCA1 missense mutations (p.Ala1708Glu, p.Gly1706Glu).…”

PPARγ against Tumors by Different Signaling Pathways

“…Skelhorne-Gross et al [5] report that PPARγ expression in mammary stromal adipocytes alleviates breast tumorigenesis through increasing expression of the breast cancer susceptibility protein, BRCA1, and decreasing serum leptin levels. PPARγ plays an essential role in colon cancer, and it is not surprising that PPARγ expression is low in colon cancer patients compared to healthy controls [6].…”