The role of PPARg-dependent microRNA expression during breast tumour metastasis
Previous studies by Dr. Nicol showed the first direct in vivo evidence that peroxisome proliferator-activated receptor (PPAR)γ normally suppresses environmental chemical 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumour progression. Our lab also used mice with targeted knockout (KO) of PPARγ in mammary secretory epithelial (MSE) cells (PPARγMSE-KO mice) and their wildtype (PPARγWT) controls to show DMBA-treated PPARγMSE-KOs had significantly worse breast tumourigenic outcomes versus PPARγWTs; whereas, co-treatment with the PPARγ activating, antidiabetic drug rosiglitazone (ROSI) significantly improves tumourigenic outcomes in PPARγWT but not PPARγMSE-KO mice. I hypothesized activation of MSE-specific PPARγ signaling alters microRNA (miR) expressions to protect against breast tumour metastasis. My aims were to: 1) use enhanced PPARγMSE-KO mice strains to evaluate MSE-specific PPARγ-dependent miR changes in mammary tumours and correlate findings with metastatic events in vivo; and 2) identify PPARγ-dependent miRs that correlate with human breast cancer cell metastatic potential in vitro. To address aim one, PPARγMSE-KO or PPARγMSE-WT mice were crossed onto an enhanced yellow fluorescent protein (EYFP) reporter mouse background to generate PPARγMSE-KO;EYFP+ and control PPARγMSE-WT;EYFP+ strains respectively, allowing for easy detection of MSE cells for miR profiling. PPARγMSE-WT;EYFP+ mice were treated with DMBA Only or DMBA+ROSI as previously described, and no significant difference was observed in overall survival (OS). Mammary tumours were collected from each treated group for evaluation of miR expressions. To address aim two, the human metastatic MDA-MB-231 breast cancer cell line was transduced to stably express PPARγ and generate both parental (MDA-MB-231parental) and PPARγ expressing (MDA-MB-231PPARγWT) cell lines. Metastatic potential was significantly decreased in MDA-MB-231PPARγWT versus MDA-MB-231parental cells, and following ROSI treatment. qRT-PCR expression changes of five miR targets implicated in tumourigenesis were selected for assessment, and revealed no significant differential expression between the treatment groups in either cell line for any of the miRs. Future studies assessing global expression changes will be critical to determine whether activation of PPARγ alters miR profiles to prevent breast cancer metastasis.
URI for this recordhttp://hdl.handle.net/1974/26070
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