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Cancers 2019, 11(4), 507;

Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer

1, 1,2,3,†, 2,3,*,‡ and 1,*,‡
College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Research Institute in Oncology and Hematology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
Authors to whom correspondence should be addressed.
Present address: Agriculture and Agri-Food Canada, Science and Technology Branch, Morden, MB R6M 1Y5, Canada
Theses authors contributed equal to this work
Received: 7 February 2019 / Revised: 2 April 2019 / Accepted: 2 April 2019 / Published: 10 April 2019
PDF [5376 KB, uploaded 11 April 2019]


Different breast cancer (BC) subtypes have unique gene expression patterns, but their regulatory mechanisms have yet to be fully elucidated. We hypothesized that the top upregulated (Yin) and downregulated (Yang) genes determine the fate of cancer cells. To reveal the regulatory determinants of these Yin and Yang genes in different BC subtypes, we developed a lasso regression model integrating DNA methylation (DM), copy number variation (CNV) and microRNA (miRNA) expression of 391 BC patients, coupled with miRNA–target interactions and transcription factor (TF) binding sites. A total of 25, 20, 15 and 24 key regulators were identified for luminal A, luminal B, Her2-enriched, and triple negative (TN) subtypes, respectively. Many of the 24 TN regulators were found to regulate the PPARA and FOXM1 pathways. The Yin Yang gene expression mean ratio (YMR) and combined risk score (CRS) signatures built with either the targets of or the TN regulators were associated with the BC patients’ survival. Previously, we identified FOXM1 and PPARA as the top Yin and Yang pathways in TN, respectively. These two pathways and their regulators could be further explored experimentally, which might help to identify potential therapeutic targets for TN. View Full-Text
Keywords: breast cancer; regulator; lasso; triple negative; PPARA; FOXM1 breast cancer; regulator; lasso; triple negative; PPARA; FOXM1

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Huang, S.; Xu, W.; Hu, P.; Lakowski, T.M. Integrative Analysis Reveals Subtype-Specific Regulatory Determinants in Triple Negative Breast Cancer. Cancers 2019, 11, 507.

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