Polyunsaturated Fatty Acids Alter the Epigenetic Landscape of Triple-Negative Breast Cancer (TNBC)
AuthorChattin, Amy M.
AdvisorPardini, Ronald S.
Biochemistry and Molecular Biology
AltmetricsView Usage Statistics
Breast cancer is the second leading cause of cancer-related deaths in US women; 10-20% of which are triple-negative breast cancer (TNBC) subtypes and have the poorest short-term prognosis. This is probably due to an epithelial to mesenchymal transition (EMT) that tumors undergo, de-differentiating into cancer stem cells. Epigenetic reprogramming is proposed to be required for malignant transformation and invasion, particularly in cells undergoing EMT transitions such as TNBC. Therefore, altering the epigenetic landscape in metastatic TNBC lines would provide researchers with a unique opportunity to sensitize tumors to treatment and induce apoptosis.Epigenetic research chiefly focuses on inhibitors of co-repressors histone deacetylase (HDACi) and DNA methyltransferases (DNMTi). Short chain fatty acids, have proven to be effective HDACi’s, suggesting a possible role for other fats in epigenetic regulation. Research has shown that several omega-3 polyunsaturated fatty acids (PUFAs), specifically docosahexaenoic acid (DHA; C22:6, n-3) and eicosapentaenoic acid (EPA; C20:5, n-3), inhibit tumorigenesis whereas the omega-6 PUFA linoleic acid (LA; 1C8:2, n-6) promotes neoplastic growth; supporting the association of elevated cancer incidence with n-6 PUFA dietary intake. We initiated studies to evaluate the impact of omega-3 fatty acids on tumor epigenetic pathways. Therefore we monitored epigenetic alterations in MDA-MB-231 TNBC cells in response to both omega-3 and omega-6 PUFAs in a time and dose-dependent manner. DHA, EPA, and arachidonic acid (AA; 20:5, n-6) all elicit apoptosis in a similar manner, indicating that initiating apoptosis is not omega-6 or omega-3 specific. We now show that PUFA incorporation and the resulting attenuated metabolism are not sufficient to induce apoptosis in MDA-MB-231 TNBC at 3 and 12 hour timepoints. Additionally, plasma membrane integrity was not appreciably altered at 3 or 12 hour time points. These data, combined with a lack apoptosis at 12 hours, indicate that the level of intact PUFA in cell membranes does not initiate apoptosis. Moreover, mitochondrial membrane potential was universally diminished early and throughout the time course and, although not limiting, decreased ATP levels were observed at 12 hours (relative to vehicle control). Furthermore, activity of HDAC classes (I, IIa and IIb) were altered early at 3 and 48 hours, but typically punctuated with a recovery to basal levels noted at the 12 hour time point. Chromatin condensation was observable primarily in 12 and 48 hour time points, although it was noted in DHA and EPA treatments at 3 hours. Collectively, these data demonstrate that PUFA-mediated epigenetic changes occur on a time scale proceeding apoptotic induction, indicating that PUFAs may be useful as an epigenetically-targeted cancer therapeutic agent or adjuvant therapy.