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

• Published in: International journal of cancer Vol. 134; no. 5; pp. 1055 - 1066
• Main Authors: Apostoli, Anthony J., Skelhorne‐Gross, Graham E.A., Rubino, Rachel E., Peterson, Nichole T., Di Lena, Michael A., Schneider, Mark M., SenGupta, Sandip K., Nicol, Christopher J.B.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01-03-2014; Wiley Subscription Services, Inc; BlackWell Publishing Ltd
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracene; Apoptosis; bcl-2-Associated X Protein - analysis; Biological and medical sciences; Breast cancer; Cancer; Carcinogenesis; chemical carcinogenesis; chemotherapy; Cyclin D1; Eotaxin; Epithelial cells; Epithelial Cells - metabolism; Female; Genotypes; Gynecology. Andrology. Obstetrics; knockout mouse model; Lactation; Latency; Mammary gland; Mammary gland diseases; Mammary Glands, Animal - metabolism; Mammary Neoplasms, Experimental - etiology; Mammary Neoplasms, Experimental - metabolism; mammary secretory epithelial cells; Medical research; Medical sciences; Mice; Mice, Knockout; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Peroxisome proliferator-activated receptors; PPAR gamma - physiology; PPARγ; Pregnancy; PTEN Phosphohydrolase - analysis; PTEN protein; RANTES; Superoxide; Tumorigenesis; Tumors; Animal model; Breast disease; chemical carcinogenesis; Secretory cell; Breast cancer; Tumorigenicity; knockout mouse model; Malignant tumor; PPAR-γ receptor; Carcinogenesis; PPARγ; Mammary gland diseases; Chemotherapy; Treatment; Cancerology; Animal; Knockout mouse; Breast; Epithelial cell; Environment; Mammary gland; mammary secretory epithelial cells; Cancer; breast cancer; chemotherapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28432

Breast cancer is the leading cause of new cancer diagnoses among women. Using peroxisome proliferator‐activated receptor (PPAR)γ(+/−) mice, we showed normal expression of PPARγ was critical to stop 7,12‐dimethylbenz[a]anthracene (DMBA)‐induced breast tumorigenesis. PPARγ 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 PPARγ was hypothesized to enhance DMBA‐mediated breast tumorigenesis. To test this, MSE cell‐specific PPARγ knockout (PPARγ‐MSE KO) and control (PPARγ‐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: PPARγ‐WT, n = 15; PPARγ‐MSE KO, n = 25) or one supplemented with a PPARγ activating drug (DMBA + ROSI: PPARγ‐WT, n = 17; PPARγ‐MSE KO, n = 24), and monitored for changes in breast tumor outcomes. PPARγ‐MSE KOs had significantly lower overall survival and decreased mammary tumor latency as compared to PPARγ‐WT controls. PPARγ activation significantly reduced DMBA‐mediated malignant mammary tumor volumes irrespective of genotype. MSE‐specific PPARγ 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, PPARγ 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 PPARγ during breast tumorigenesis, and support a novel chemotherapeutic role of PPARγ activation in breast cancer.
What's new?
PPARγ is a transcription factor that has been implicated in several types of cancer, including breast cancer. In this study, the authors examined the role of PPARγ during breast tumorigenesis in mice, and found that it has a significant protective effect. Drugs that activate PPARγ may thus provide a new chemotherapeutic option for breast cancer patients, especially during the postpregnancy period when risk is transiently increased.