Premium
Hyperinsulinemia Induced Changes in Chromatin Acetylation and Gene Expression in Triple Negative Breast Cancer
Author(s) -
Senapati Parijat,
Ann David K.,
Seewaldt Victoria,
Schones Dustin E.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb61
Subject(s) - hyperinsulinemia , cancer research , triple negative breast cancer , pi3k/akt/mtor pathway , biology , insulin receptor , insulin resistance , chromatin , medicine , endocrinology , insulin , microbiology and biotechnology , signal transduction , cancer , breast cancer , genetics , gene
Triple negative breast cancer (TNBC), characterized by lack of expression of the estrogen receptor (ER) and progesterone receptor (PR) and absence of HER2 amplification, is a particularly aggressive breast cancer subtype, constituting about 15–20% of all breast cancers. Premenopausal women of African descent have a high risk for TNBC, especially those with higher body mass index (BMI). Moreover, obesity associated hyperinsulinemia or insulin‐resistance is considered as a poor prognostic factor for TNBC patients. Insulin signaling can activate the PI3K/Akt/mTOR pathway that is associated with increased proliferation rate of TNBC cells. However, the mechanistic role of insulin resistance in promoting TNBC is unclear. We are particularly interested in studying how insulin signaling impinges on mitochondrial dysfunction and nuclear gene expression through the mTOR pathway. mTOR signaling activates oxidative phosphorylation by the mitochondria thereby potentially increasing Acetyl‐CoA production through the TCA cycle. Nuclear histone acetyltransferases utilize acetyl‐CoA as a substrate to acetylate histones, leading to increased chromatin accessibility and gene expression. We show here that insulin treatment to the MDA‐MB‐231 TNBC cell line leads to increases in global histone acetylation levels, in particular H3K9ac, and altered expression of several genes. Transcriptome analysis along with H3K9ac ChIP‐sequencing reveal rewiring of cells towards anabolic processes such as DNA and protein synthesis. Insulin treatment furthermore induced cell proliferation and survival related pathways. Future studies will be focused on studying the molecular mechanism of insulin induced chromatin hyperacetylation and possible reversal by metformin.