Seed in soil, with an epigenetic view

Abstract

It is becoming increasingly evident that discrete genetic alterations in neoplastic cells alone cannot explain multistep carcinogenesis whereby tumor cells are able to express diverse phenotypes during the complex phases of tumor development and progression. The epigenetic model posits that the host microenvironment exerts an initial, inhibitory constraint on tumor growth that is followed by acceleration of tumor progression through complex cell-matrix interactions. This review emphasizes the epigenetic aspects of breast cancer development in light of such interactions between epithelial cells ("seed") and the tumor microenvironment ("soil"). Our recent research findings suggest that epigenetic perturbations induced by the tumor microenvironment may play a causal role in promoting breast cancer development. It is believed that abrogation of these initiators could offer a promising therapeutic strategy.

Fig. 1

An epigenetic model depicting the influence of breast cancer-associated fibroblasts on the non-cancerous breast epithelial cells (MCF10A). (A) After cocultured with cancer-associated fibroblasts (CAF), CST-6 (and perhaps other breast cancer-associated genes) became hypermethylated and silenced (marked in red). Epigenetic perturbation was mediated by an activation of AKT1 signaling pathway. (B) In contrast, exposure to normal fibroblasts (NF) confers negligible levels of epigenetic perturbations and AKT1 kinase activation in the same MCF10A cells (marked in light blue).