Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression

Abstract

BackgroundAmong women worldwide, breast cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related deaths. Improved understanding of breast tumourigenesis may facilitate the development of more effective therapies. Peroxisome proliferator-activated receptor (PPAR)γ is a transcription factor that regulates genes involved in insulin sensitivity and adipogenesis. Previously, we showed, using 7,12-dimethylbenz [a] anthracene (DMBA)-treated haploinsufficient PPARγ mice, that PPARγ suppresses breast tumour progression; however, the PPARγ expressing cell types and mechanisms involved remain to be clarified. Here, the role of PPARγ expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated.MethodsPPARγ MG knockout (PPARγ-MG KO) mice and their congenic, wild-type controls (PPARγ-WT) were treated once a week for six weeks by oral gavage with 1 mg DMBA dissolved in corn oil and maintained on a normal chow diet. At week 7, mice were randomly divided into those maintained on a normal chow diet (DMBA Only; PPARγ-WT: n = 25 and PPARγ-MG KO: n = 39) or those receiving a diet supplemented with the PPARγ ligand, rosiglitazone (ROSI, 4 mg/kg/day) (DMBA + ROSI; PPARγ-WT: n = 34 and PPARγ-MG KO: n = 17) for the duration of the 25-week study.ResultsCompared to DMBA Only-treated PPARγ-WTs, both breast tumour susceptibility and serum levels of proinflammatory and chemotactic cytokines, namely IL-4, eotaxin, GM-CSF, IFN-γ, and MIP-1α, were decreased among PPARγ-MG KOs. Cotreatment with ROSI significantly reduced breast tumour progression among PPARγ-WTs, correlating with increased BRCA1 and decreased VEGF and COX-2 protein expression levels in breast tumours; whereas, surprisingly DMBA + ROSI-treated PPARγ-MG KOs showed increased breast tumourigenesis, correlating with activation of COX-2.ConclusionThese novel data suggest MG-specific PPARγ expression and signaling is critical during breast tumourigenesis, and may serve as a strong candidate predictive biomarker for response of breast cancer patients to the use of therapeutic strategies that include PPARγ ligands.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0347-8) contains supplementary material, which is available to authorized users.

TNBG-5602, a novel derivative of quinoxaline, inhibits liver cancer growth via upregulating peroxisome proliferator-activated receptor γ in vitro and in vivo

“…[33][34][35] Some synthetic PPARc ligands, such as rosiglitazone, troglitazone and ciglitazone, inhibit the proliferation of tumour cells and induce tumour cell apoptosis. [36][37][38][39][40] In this study, we found that TNBG-5602 can increase the expression of PPARc at the mRNA and protein levels in vitro and in vivo. Further study found that a PPARc agonist (RSG) can enhance the lipid accumulation of TNBG-5602, while a PPARc inhibitor (T0070907) can reverse the lipid accumulation of TNBG-5602.…”

“…It was discovered that overexpression of PPARγ can inhibit cell proliferation and tumour growth, while it is reversed in PPARγ‐silenced cancer cells . Some synthetic PPARγ ligands, such as rosiglitazone, troglitazone and ciglitazone, inhibit the proliferation of tumour cells and induce tumour cell apoptosis …”

PPARδas a Metabolic Initiator of Mammary Neoplasia and Immune Tolerance

“…PPAR γ agonists reduce mammary carcinogenesis [17–19], which correlates with induction of PTEN [20, 21] and BRCA1 [22] tumor suppressor activity, as well as reduction of inflammation via the Cox2/Ptgs2 pathway [23]. Conversely, PPAR γ haploinsufficiency [23] or expression of a dominant-negative Pax8-PPAR γ transgene [24] and direct or indirect inhibition of PPAR γ [21, 25] enhance DMBA mammary carcinogenesis. In MMTV-Pax8-PPAR γ mice, the increased rate of carcinogenesis correlates with enhanced Wnt, Ras/Erk, and PDK1/Akt signaling, reduced PTEN expression, and a more stem cell-like phenotype [24].…”

New Predictor Model for Classification Anti-breast cancer Compounds According to Multiple Parameters

“…In this study, some proteins that were found to be related to breast cancer and used in this QSAR are Breast cancer type 1 susceptibility protein, Peroxisome proliferator-activated receptor gamma, STE20-related kinase adapter protein alpha, ATP-binding cassette sub-family G member 2, Human breast cancer cell lines, and Nuclear receptor coactivator 3 (3).…”

“…It has also been found that this gene product initiates cancerous cell migration. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression (3).…”