Abstract 110: PPARγ loss increases the metastatic potential of HER2+ breast cancer

Abstract

Breast tumors that overexpress human epidermal growth factor receptor 2 (HER2+) grow and spread faster than HER2-negative tumors, resulting in poor patient prognosis. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear transcription factor that controls the expression of genes essential for normal metabolism of fats and sugars in the body. Our laboratory previously showed that PPARγ expression suppresses environmental carcinogen DMBA-mediated breast tumor progression in vivo, and PPARγ-activating drugs further enhance this effect. However, the role of PPARγ and PPARγ agonists on HER2+ breast tumorigenesis and patient survival is unclear. We hypothesized that PPARγ loss enhances HER2+ breast tumor progression. To test this, this study generated a novel mouse model referred to as NIC:PPARγ-KO, which has targeted PPARγ deletion in the same HER2+ transformed mammary epithelial cells that drive breast tumorigenesis. Compared to NIC:PPARγ-WT mice, NIC:PPARγ-KO mice have increased mammary tumor incidences and lung metastases. Protein analysis of NIC:PPARγ-KO tumors shows PPARγ loss is inversely correlated with increased HER2 phosphorylation at tyrosine 877 (pY877HER2) in primary and metastatic tumorigenic tissue. Immunofluorescence also showed HER2 H-scores were significantly highest among tumors from NIC:PPARγ-KO mice, but also correlated with targeted PPARγ loss in DMBA-induced primary and metastatic mammary tumors among PPARγ-WT and PPARγ-KO mice (p<0.05). To further investigate the role of PPARγ in the metastatic process, we established cell lines from the freshly isolated lung metastatic tumors harvested from the NIC:PPARγ-KO model (NIC:PPARγ-KO-lmet). In vitro analysis of several human HER2+ breast cancer cells lines and our NIC:PPARγ-KO-lmet cells shows migration, invasion and tumorsphere-forming potential were significantly increased after epidermal growth factor (EGF, 20ng/mL) treatment and, more interestingly, that co-treatment with a PPARγ-activating drug (rosiglitazone, 10μM) significantly abrogated these effects (p<0.05). Together, these data provide the first evidence that PPARγ may be a useful prognostic/predictive biomarker for HER2+ breast tumors, and suggest that the novel inclusion of PPARγ-activating drugs may benefit a subset of HER2+ breast cancer patients. Citation Format: Elizabeth D. Lightbody, Kathleen MJ O'Connell, Hailey T. Newton, Rachel R. Rubino, Anthony J. Apostoli, Kevin Ren, Sandip K. SenGupta, Christopher J. Nicol. PPARγ loss increases the metastatic potential of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 110.

The initial expression alterations occurring to transcription factors during the formation of breast cancer: Evidence from bioinformatics

“…PPARG constitutes heterodimer with retinoid X receptor and thus conducts transcription of multiple genes, which mainly regulates adipocyte differentiation and is related to cancer, inflammation, and atherosclerosis. 84 In BC, researches indicated that PPARG inhibited tumor progression 85 , 86 , 87 as a promising antineoplastic agent in the clinic. 88 …”