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.
Highlights
Women who harbor a heterozygous germline mutation in BRCA1/2 face an extremely high risk of breast and ovarian cancer but rarely that of other cancers [1]
One of these breast-specific differentially methylated regions (DMRs) was located at the internal promoter of the TP73 gene, which controls the expression of the N-terminus truncated variant deltaNp73
Analysis of the array results at this locus revealed that the deltaNp73 promoter (P2) was hypomethylated (50%) in breast compared to normal endometrial, lung, and colon epithelium as well as peripheral white blood cells
Summary
Women who harbor a heterozygous germline mutation in BRCA1/2 face an extremely high risk of breast and ovarian cancer but rarely that of other cancers [1]. The BRCA1/2 proteins play a prominent role in DNA repair by homologous recombination, cell cycle control, and maintenance of genome integrity in all cells [2]. It is, not clear why disruption of this universal mechanism predisposes to cancer almost exclusively in the breast and ovary. It has been suggested that tissue-specific features affecting differentiation and transcriptional regulation [5,6], or the local effect of estrogen and other secreted factors [7,8], may team up with BRCA deficiency to support carcinogenesis. The body of evidence to date does not fully explain BRCA-related tissue-specific cancer susceptibility [10,11,12]
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