Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasisin vivo; therapeutic and chemopreventive applications

// Niaz Mahmood 1 , David Cheishvili 2 , Ani Arakelian 1 , Imrana Tanvir 3 , Haseeb Ahmed Khan 3 , Anne-Sophie Pépin 2 , Moshe Szyf 2 and Shafaat A. Rabbani 1 1 Department of Medicine, McGill University Health Centre, Montréal, Canada 2 Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada 3 Department of Pathology, Fatima Memorial Hospital, Lahore, Pakistan Correspondence to: Shafaat A. Rabbani, email: shafaat.rabbani@mcgill.ca Keywords: DNA methylation; breast cancer; metastasis; SAM; epigenetics Received: August 08, 2017      Accepted: December 01, 2017      Published: December 26, 2017 ABSTRACT DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S-adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro . These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality.