both in vitro and in vivo. based on these results, it was concluded that tcf21 is a tumor suppressor gene, often silenced by hypermethylation in cancer. tcf21 has also been linked to metastatic melanoma progression through the inhibition of the kiss1 metastasis-suppressor gene. dna methylation analysis in melanoma patient biopsies has demonstrated downregulation of tcf21 due to promoter hypermethylation, which also correlates with decreased survival in patients suffering from metastatic skin melanoma. tcf21, together with e12 and tcf12, bind the kiss1 promoter, sustaining its activity. without tcf21 to interact with the kiss1 promoter, kiss1 expression is lost. melanoma cells overexpressing tcf21 have also been found to display reduced motility compared with vector-only control cells. tobacco-induced lung cancer research has found tcf21 to be among the genes identified as highly methylated at both high and low concentrations of cigarette smoke condensate (csc). in the presence genistein, one of the soy-derived bioactive isoflavones, methylation of tcf21 is significantly reduced. genistein has been known to affect tumorigenesis through epigenetic regulation, such as chromatin configuration and dna methylation, activating other tumor suppressor genes that affect cancer cell survival. these findings support the hypothesis that increasing hypermethylated tumor suppressor genes such as tcf21 is a potential chemopreventative pathway in tobacco-induced lung cancer. tcf21 may have also therapeutic potential for breast cancer treatment, as downregulation of tcf21 has been implicated in breast cancer tumorigenesis and proliferation. tcf21 mrna expression is very low in breast cancer cells compared with normal breast epithelial cells. this low expression is also associated with large tumor size and lymph node metastasis. breast cancer tissues exhibit significantly downregulated expression of tcf21 mrna and tcf21 mrna overexpression has been found to inhibit cancerous cell proliferation. clinical marker tcf21 methylation has been considered as a potential clinical marker in the diagnosis of renal cell carcinoma. accordingly, tcf21 methylation levels in urine samples may be a useful means of diagnosing renal cell carcinoma. also tcf21 rs12190287 polymorphism can regulate tcf21 expression and may serve as a potential marker for genetic susceptibility to breast cancer. additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the tcf21 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. the study was based on a community cohort study (the malmo diet and cancer study) and four additional randomized controlled trials of primary prevention cohorts (jupiter and ascot) and secondary prevention cohorts (care and prove it-timi 22).