Germline mutations in the BRCA1, BRCA2, PTEN, or TP53 tumor suppressor genes indicate that 5-10% of breast cancers (BCs) are familial. These genes may accumulate somatic mutations in conjunction with mutations and/or amplifications of PIK3CA and AKT3, as well as deletions or mutations of PTEN, TSC1, and INPP4B in the PI3K/mTOR pathway, although not in the majority of BCs. Indeed, none of them have been directly established as a sole driver gene capable of inducing the entire process of transforming epithelial cells into breast cancer.
In a recent paper published in Molecular Cancer (Cifuentes et al. 2024; doi: 10.1186/s12943-024-02054-3), we show that the oncogene RRAS2, of the RAS family, is overexpressed without mutation in a large majority of human breast cancers, especially of the triple-negative type. We suggest a cause-effect relationship because overexpression of RRAS2 in the mouse mammary gland leads to breast ductal adenocarcinomas in all female mice but, interestingly, only in breeders. This finding shows that overexpression of wild-type RRAS2 is sufficient to provoke the development of breast cancer. The association with pregnancy was confirmed in the human patient cohort: RRAS2 expression was highest in the tumors of the youngest patients and, within those, in tumors isolated from young parous women. Highest RRAS2 expression was also correlated with worse prognostic factors, such as a high percentage of Ki67+ cells, loss of p53, and most importantly, reduced life expectancy after diagnosis. Finally, the frequency of a SNP in the 3′ untranslated region of the RRAS2 gene and the finding of gene amplification in tumor samples and blood from breast cancer patients strongly suggest a causative link between RRAS2 overexpression and this disease.
Unmutated RRAS2 Emerges as a Key Oncogene in Post-partum-associated Triple Negative Breast Cancer
