Abstract 4536: Polyunsaturated fatty acids alter the epigenetic landscape in triple-negative breast cancer (TNBC)

Abstract

Abstract Breast cancer is the second leading cause of cancer-related deaths in US women. The lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor II (HER2) in basal-like breast cancer subtypes, commonly referred to as triple-negative breast cancer (TNBC), account for 10-20% of cases and are associated with the poorest short-term prognosis due to a lack of targeted therapies. Epigenetic therapies are currently of interest to target TNBC, as many theorize epigenetic reprogramming is required for malignant transformation and invasion. Research has shown omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA; C22:6, n-3) and eicosapentaenoic acid (EPA; C20:5, n-3) inhibit tumorigenesis, whereas linoleic acid (LA; C18:2, n-6) has been shown to promote neoplastic growth; supporting the association of increased cancer incidence with omega-6 PUFA dietary intake. Arachidonic acid (AA; C20:4, n-6) is associated with pro-inflammatory signaling processes, and therefore tumorigenesis; however, conflicting results exist in the literature across tumor types. PUFAs are bioactive nutrients known to have epigenetic effects within normal cells and recently, the ability of PUFA to alter DNA methylation and histone acetylation was reported in HCT-116 colon carcinoma (Cho, Y. et al, 2014). Current research focuses on the potential of dietary intervention in TNBC as an epigenetic therapy. This study monitors epigenetic alterations in MDA-MB-231 TNBC in response to DHA, LA, EPA and AA. DHA, EPA and AA all elicit similar levels of apoptosis in MDA-MB-231, while LA promotes tumorigenesis. Initial results demonstrate promoter methylation changes (p<0.05) with a decrease in PTGS2 (prostaglandin-endoperoxidase synthase 2), and SOCS1(suppressor of cytokine signaling 1) and an increase in CDX2 (caudal type homeobox 2), HIC1 (hypermethylated in cancer 1), SPARC (Secreted Protein, Acidic, Cysteine-Rich (Osteonectin)), TSC1 (tuberous sclerosis 1), and WIF1 (WNT inhibitory factor 1) post DHA treatment. Studies are on-going to assess if the promoter methylation changes result in transcriptome and proteome level fluctuations. We are also investigating global gDNA methylation alterations, including 5-methylcytosine, in response to treatment. DHA, EPA, LA and AA exhibit dose-dependent effects on histone acetylation and HDAC class I/II activity. There is an increase in HDAC class I/II activity with the EC75, but not with the EC50 treatment for all PUFAs. Histone 3 global acetylation is decreased for all PUFA treatments at the EC75 versus EC50 dose. However, only LA and DHA have decreased H3 acetylation with an EC75 dose whereas EPA and AA have increased acetylation levels compared to the control. Research is ongoing to define a possible mechanism, but current data suggests PUFA may be useful as epigenetically-targeted cancer therapeutic agent or adjuvant. Citation Format: Amy M. Chattin, Mykelti O’Brien, Ronald S. Pardini. Polyunsaturated fatty acids alter the epigenetic landscape in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4536.