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

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.

Mapping breast tissue types by miniature radio-frequency near-field spectroscopy sensor in ex-vivo freshly excised specimens.

BACKGROUND: Receiving real-time information on tissue properties while performing biopsy procedures has the potential of improving biopsy accuracy. The study goal was to test the ability of a miniature flexible Radio-Frequency (RF) sensor (Dune Medical Devices), designed to be mounted on the surface of surgical tools, in measuring and mapping the various breast tissue types and abnormalities in terms of electrical properties. METHODS: Between January and October 2012, 102 patients undergoing lumpectomy, open-biopsy or mastectomy, in 3 medical centers, were enrolled in this study. The device was applied to freshly excised specimens, with registration between device measurements and histology analysis. Based on histology, the dielectric properties of the various tissue types were derived. Additionally, the ability of the device to differentiate between malignant and non-malignant tissue was assessed. RESULTS: A total of 4322 measurements from 106 specimens from 102 patients were analyzed. The dielectric properties of 10 tissue types in the low RF-frequency range were measured, showing distinct differences between the various types. Based on the dielectric properties, a score variable was derived, which showed a correlation of 90 % between the RF measurements and the tissue types. Differentiation ability between tissue types was characterized using ROC curve analysis, with AUC of 0.96, and sensitivity and specificity of 90 and 91 % respectively, for tissue feature sizes at or above 0.8 mm. CONCLUSIONS: Using a radio-frequency near-field spectroscopy miniature flexible sensor the dielectric properties of multiple breast tissue types, both normal and abnormal, were evaluated. The results show promise in differentiating between various breast tissue types, and specifically for differentiation between cancer and normal tissues.

The characteristics of malignant breast tumors in hormone replacement therapy users versus nonusers.

BACKGROUND: The purpose of this study was to investigate the characteristics of breast cancer in hormone replacement therapy (HRT) users vs. nonusers. METHODS: We investigated the characteristics of all patients between the ages of 50 and 75 years with breast tumors. Then, an age-adjusted group of 55 nonusers was chosen to match and compare with HRT users. RESULTS: Of the 243 patients available for evaluation, 55 (22.6%) used HRT. Disease stages in HRT users vs. nonusers were as follows: ductal carcinoma in situ (DCIS), 20% and 17.1%; stage I, 45.5% and 41.7%; stage II, 30.9% and 26.2%; stage III, 3.6% and 13.4%; and stage IV, 0% and 1.6% (P =.27). In the age-adjusted cohort, stages in nonusers were as follows: DCIS, 7.3%; stage I, 47.3%; stage II, 25.5%; stage III, 20%; and stage IV, 0% (P =.03). Tumor grades in HRT users vs. nonusers were as follows: grade I, 30.4% and 15.7%; grade II, 52.2% and 52.2%; and grade III, 17.4% and 32.1% (P =.035). Grades in cohort nonusers were as follows: I, 13.2%; II, 52.8%; and III, 34% (P =.05). In the invasive tumors, the positive estrogen receptor (ER) rates were 81.6% and 85.7% (P =.89); positive progesterone receptor (PR) rates were 53.1% and 54% (P =.95); and Her 2-neu positive rates were 18.4% and 17.6% (P =.95), respectively. No significant difference was found in intratumor DCIS, vascular invasion, and Ki-67 (P =.14,.9, and.79, respectively). The rate of lobular and favorable histological types was higher in the HRT user group: 26.6% vs. 15%. CONCLUSIONS: Breast tumors in HRT users vs. nonusers were of a significantly lower stage and grade and accounted for a higher number of favorable histological types, but all other parameters were similar in the two groups.