Loss of PPARγ expression in mammary secretory epithelial cells creates a pro-breast tumorigenic environment

Breast cancer is the leading cause of new cancer diagnoses among women. Using peroxisome proliferator-activated receptor (PPAR)((+/-)) mice, we showed normal expression of PPAR was critical to stop 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumorigenesis. PPAR is expressed in many breast cell types including mammary secretory epithelial (MSE) cells. MSEs proliferate as required during pregnancy, and undergo apoptosis or reversible transdifferentiation during involution once lactation is complete. Thus, MSE-specific loss of PPAR was hypothesized to enhance DMBA-mediated breast tumorigenesis. To test this, MSE cell-specific PPAR knockout (PPAR-MSE KO) and control (PPAR-WT) mice were generated, mated and allowed to nurse for three days. One week after involution, dams were treated with DMBA to initiate breast tumors, and randomized on week 7 to continue receiving a normal chow diet (DMBA Only: PPAR-WT, n = 15; PPAR-MSE KO, n = 25) or one supplemented with a PPAR activating drug (DMBA + ROSI: PPAR-WT, n = 17; PPAR-MSE KO, n = 24), and monitored for changes in breast tumor outcomes. PPAR-MSE KOs had significantly lower overall survival and decreased mammary tumor latency as compared to PPAR-WT controls. PPAR activation significantly reduced DMBA-mediated malignant mammary tumor volumes irrespective of genotype. MSE-specific PPAR loss resulted in decreased mammary gland expression of PTEN and Bax, increased superoxide anion production, and elevated serum eotaxin and RANTES, creating a protumorigenic environment. Moreover, PPAR activation in MSEs delayed mammary tumor growth in part by down-regulating Cox-1, Cox-2 and cyclin D1. Collectively, these studies highlight a protective role of MSE-specific PPAR during breast tumorigenesis, and support a novel chemotherapeutic role of PPAR activation in breast cancer.