Like all cancers, breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. This review will briefly discuss basic aspects of DNA methylation, recent advances in DNA methyltransferases, the role of altered chromatin organization and the concept of gene transcriptional regulation built on methylated CpGs. In particular, we discuss epigenetic regulation of certain critical tumor suppressor and growth regulatory genes implicated in breast cancer, and its relevance to breast cancer diagnosis, prognosis, progression and therapy.

Estrogen receptor alpha (ER) is an epigenetically regulated gene. Inhibitors of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) synergistically activate the methylated ER gene promoter in ER-negative MDA-MB-231 human breast cancer cells. Chromatin immunoprecipitation was used to examine the chromatin status and repressor complex associated with silenced ER and changes in the key regulatory factors during reactivation by inhibitors of DNMT (5-aza-2'-deoxycytidine) and HDAC (trichostatin A). The silencing of ER due to CpG hypermethylation correlates with binding of specific methyl-binding proteins, DNMTs, and HDAC proteins. Inhibition of HDAC activity by trichostatin A results in the accumulation of hyperacetylated core histones. The activation of ER gene expression by 5-aza-2'-deoxycytidine also involves the release of the repressor complex involving various methyl-binding proteins, DNMTs, and HDAC1. HDAC and DNMT inhibitors modulate histone methylation at H3-K9 and H3-K4 to form a more open chromatin structure necessary for reactivation of silenced ER transcription. Together these results impart a better understanding of molecular mechanisms of chromatin remodeling during ER reactivation by DNMT and HDAC inhibitors. These findings will aid in the application of agents targeting epigenetic changes in the treatment of breast cancer.

Metabolic interaction between cancer-associated fibroblasts (CAFs) and colorectal cancer (CRC) cells plays a major role in CRC progression. However, little is known about lipid alternations in CAFs and how these metabolic reprogramming affect CRC cells metastasis. Here, we uncover CAFs conditioned medium (CM) promote the migration of CRC cells compared with normal fibroblasts CM. CAFs undergo a lipidomic reprogramming, and accumulate more fatty acids and phospholipids. CAFs CM after protein deprivation still increase the CRC cells migration, which suggests small molecular metabolites in CAFs CM are responsible for CRC cells migration. Then, we confirm that CRC cells take up the lipids metabolites that are secreted from CAFs. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, is significantly increased in CAFs. CAF-induced CRC cell migration is abolished by knockdown of FASN by siRNA or reducing the uptake of fatty acids by CRC cells by sulfo-N-succinimidyloleate sodium in vitro and CD36 monoclonal antibody in vivo. To conclude, our results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.

Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.