Loss of PPARγ expression in mammary secretory epithelial cells creates a pro-breast tumorigenic environment
| Autor: | Michael Di Lena, Graham Skelhorne-Gross, Sandip SenGupta, Rachel E. Rubino, Anthony J. Apostoli, Christopher J. Nicol, Nichole Peterson, Mark M. Schneider |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_specialty PPARγ Carcinogenesis 9 10-Dimethyl-1 2-benzanthracene Mammary gland Peroxisome proliferator-activated receptor DMBA Biology medicine.disease_cause chemotherapy chemical carcinogenesis Mice Cyclin D1 Breast cancer breast cancer Mammary Glands Animal Internal medicine medicine PTEN Animals mammary secretory epithelial cells skin and connective tissue diseases bcl-2-Associated X Protein chemistry.chemical_classification Mice Knockout Mammary tumor PTEN Phosphohydrolase Mammary Neoplasms Experimental Epithelial Cells medicine.disease 3. Good health knockout mouse model body regions PPAR gamma medicine.anatomical_structure Endocrinology Oncology chemistry biology.protein Female |
| Zdroj: | International Journal of Cancer. Journal International du Cancer |
| ISSN: | 1097-0215 0020-7136 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text