Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells

Abstract

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women.

Analyzing cancer gene expression data through the lens of normal tissue-specificity

“…The limitations of paired tumor/normal data analysis motivate the exploration of associations between the general features of normal tissues, as measured in healthy individuals, and the characteristics of the cancer types that can develop in those tissues. While many researchers have investigated the association between normal tissue biology and cancer development in the context of specific cancer types and the associated cancer drivers (e.g., the association between estrogen sensitive tissues, BRCA1/BRCA2 mutations and cancer development [ 9 , 16 , 17 ]), only a limited number of researchers have explored the genome-wide association between normal tissue and cancer gene activity across multiple cancer types. The most prominent recent investigation into the general relationship between normal tissue and cancer gene activity is the work by the Uhlen et al [ 18 ], who analyzed the association between gene expression in human solid tumors profiled by the TCGA and the corresponding normal tissues profiled by the Human Protein Atlas (HPA) [ 19 ].…”