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.
Highlights
Despite the advancements being made in our understanding of the biology, diagnosis, prevention, and treatment of cancer, metastasis remains the dominant cause of breast cancer-associated morbidity and mortality [1]
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
Some other cancer-related genes that are induced by DNA hypomethylation include heparanase (HPSE) [10], synuclein-γ (SNCG) [11], pro-opiomelanocortin (POMC) [12], cadherin 3 (CDH3) [13], related RAS viral oncogene homolog (R-RAS) [14], maspin [15], and S100 calcium binding protein P (S100P) [15]
Summary
Despite the advancements being made in our understanding of the biology, diagnosis, prevention, and treatment of cancer, metastasis remains the dominant cause of breast cancer-associated morbidity and mortality [1]. The 10-year survival rate for Stage III and IV cancer patients with metastatic spread of breast tumors is 40% and less than 10% respectively [2]. There is an urgent need for the development of novel and less toxic therapeutic strategies that can be useful to block both tumor growth and metastatic spread of cancer cells. Pharmacological inhibition of methylation of non-invasive breast cancer cell lines (MCF-7, ZR-75-1) by using 5-Aza-2 ́-deoxycytidine increased the expression of prometastatic genes like PLAU, HPSE, C-X-C motif chemokine receptor 4 (CXCR4), and SNCG, and thereby transformed them into more invasive cells [16]. It stands to reason that the use of inhibitors targeting hypomethylation to downregulate genes of the metastatic cascade may serve as a suitable anti-cancer therapeutic strategy
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