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

Cancers

卷:12

TanirM. Allweis¹  SeanSoonweng Cho²  Saraswati Sukumar²  Ella Evron³  Avishay Sella⁴  Susanna Feldman⁴  Ayala Kol⁴  Ayelet Avraham⁴  Emmanuela Riklin-Nahmias⁵  Lior Heler⁶  Tamar Karni⁷ 

[1] Department of General Surgery, Kaplan Medical Center, Rehovot and the Faculty of Medicine, The Hebrew University, Jerusalem 7661041, Israel;

[2] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA;

[3] Department of Oncology, Kaplan Medical Center, Rehovot and the Faculty of Medicine, The Hebrew University, Jerusalem 7661041, Israel;

[4] Department of Oncology, Shamir Medical Center affiliated to Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo 7033001, Israel;

[5] Department of Pathology, Shamir Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo 7033001, Israel;

[6] Department of Plastic Surgery, Shamir Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo 7033001, Israel;

[7] Department of Surgery, Shamir Medical Center and the Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo 7033001, Israel;

关键词: BRCA-mutation;    cancer susceptibility;    deltaNp73;    DNA methylation;    tissue-specificity;   

DOI  :  10.3390/cancers12092367

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown