It is demonstrated that RARB5’-region hypermethylation is responsible for suppression of RARB expression in different kinds of cancers (Seewaldt et al. 1995; Liu et al. 1996; Widschwendter et al. 2001; Youssef et al. 2004; Ivanova et al. 2002; Wang et al. 2003; Uray et al. 2009; Twelves et al. 2013; Lotan et al. 1995; Molinari et al. 2013; Cosialls et al. 2012; Chung et al. 2011). It presumably shed light to the important preventive and therapeutic role of retinoids in treatment of cancer. It is investigated that hypermethylated RARB is associated with diagnosis of breast cancer at younger age, with no family history (Pirouzpanah et al. 2010; Mehdipour et al.), high histological grade, high proliferation, increased tumor size, and metastasis (Marzese et al. 2012). In lung cancer, several alterations have been demonstrated in RARB (Gebert et al. 1991). Mutation in RARB is also shown to be associated to microphtalmia (Chitayat et al. 2007; Srour et al. 2013; Chassaing et al. 2013). Recessive and dominant mutations in RARB has shown to cause microphtalmia and diaphragmatic hernia, by loss or gain of function, respectively (Srour et al. 2013). In melanoma, it is shown that RAR-β interacts with p14^ARF and plays roles toward the irreversible growth inhibition of malignant cells, therefore treatment of melanoma (Dahl et al. 2013). In Helicobacter Pylori derived gastric cancer, RARB is among genes with reduced expression levels, presumably regulated by epigenetic mechanisms (Cheng et al. 2013). Interestingly among risk factors, benzo(α) pyrene diol epoxide (BPDE) which is a carcinogen present in tobacco and environmental pollution in esophageal cancer, and bile acid which is an oncogene in gastrointestinal cancers, inhibit the expression of RARB (Song et al. 2005; Song and Xu 2001; Li et al. 2002). Methylation pattern of RARB in esophageal squamous cell carcinoma correlates with the development and severity of the disease (Li et al. 2014). Notably, BPDE induces miR-16-2, and as noted above, inhibits RARB (Hu et al. 2011). Unlike, the methylation pattern of RARB is lower in cancer stem cell rich populations of breast tumor (Park et al. 2012), which may play roles in lower proliferation rate of cancer stem cells.

Manipulation of methylation pattern of RARB is getting to be an interesting clinical procedure. Investigating the methylation pattern of RARB has been suggested to be a non-invasive biomarker for the prevention and diagnosis of prostate cancer (Gao et al. 2013). Genetic imbalance in the region containing RARB, on the other hand, has been shown to be a valuable target for personalized medicine (Ribeiro et al. 2014). Interestingly, epigenetic reprogramming seems to have considerable impact on tumor reversion, introducing epigenetic therapy. Axolotl extracts from oocyte reverses the epigenetic silencing of RARB, and therefore tumorigenicity of breast cancer cells, by arresting tumor growth (Allegrucci et al. 2011).