hMSH2, XRCC1, and hOGG1, were heavily methylated and both the messenger RNA and proteins of these DNA repair genes were progressively reduced. DNA damage also increased with Cd-induced transformation. Reduction of protein expression of ERCC1 in progression to sporadic cancer is unlikely to be due to mutation. While germ line (familial) mutations in DNA repair genes cause a high risk of cancer (see inherited impairment in DNA repair increases cancer risk), somatic mutations in DNA repair genes, including ERCC1, only occur at low levels in sporadic (non-familial) cancers. Control of ERCC1 protein level occurred at the translational level. In addition to the wild-type sequence, three splice variants of mRNA ERCC1 exist. ERCC1 mRNA is also found to have either wild-type or three alternative transcription start points. Neither the level of overall mRNA transcription, splice variation nor transcription start point of mRNA correlates with protein level of ERCC1. The rate of ERCC1 protein turnover also does not correlate with ERCC1 protein level. A translational level control of ERCC1, due to a microRNA (miRNA), has been shown during HIV viral infection. A trans-activation response element (TAR) miRNA, coded for by the HIV virus, down-regulates ERCC1 protein expression. TAR miRNA allows ERCC1 mRNA to be transcribed, but acts at the p-body level to prevent translation of ERCC1 protein. (A p-body is a cytoplasmic granule “processing body” that interacts with miRNAs to repress translation or trigger degradation of target RNAs.) In breast cancer cell lines, almost one third (55/167) of miRNA promoters were targets for aberrant methylation (epigenetic repression). In breast cancers themselves, methylation of let-7a-3/let-7b miRNA in particular was found. This indicates that let-7a-3/let-7b can be epigenetically repressed. Repression of let-7a can cause repression of ERCC1 expression through an intermediary step involving the HMGA2 gene. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present. (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are chromatin architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing local DNA conformation. Regulation is achieved by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. HMGA2