The risk of developing breast cancer by age 50 in BRCA-positive women has increased from 24% in women born before 1940 to 67% in women born after 1940. This observation points to an increase in one or more environmental promoters through the course of the twentieth century. Extrapolating backwards, it is possible that, in the nineteenth century, a BRCA mutation conferred minimal increased risk ...

PARP inhibitors are considered promising anticancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCA1 or BRCA2 mutat...

The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3- to 8-fold greater relative biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. As alpha particles typically cause DNA double-strand breaks (DSB), tar...

About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers – 4 to 8 and 10 to 20 fold higher respectively. Due to the small ...

PURPOSE The incidence of bone metastasis in advanced breast cancer (BrCa) exceeds 70%. Bortezomib, a proteasome inhibitor used for the treatment of multiple myeloma, also promotes bone formation. We tested the hypothesis that proteasome inhibitors can ameliorate BrCa osteolytic disease. EXPERIMENTAL DESIGN To address the potentially beneficial effect of bortezomib in reducing tumor growth in ...

Homologous recombination (HR) and base excision repair (BER) are two of the major DNA-repair pathways. The proteins encoded by breast-related cancer antigen (BRCA) and poly(adenosine diphosphate-ribose) polymerases (PARP) are involved in HR and BER, respectively. Tumors with HR deficiency, including those in BRCA mutation carriers, are sensitive to BER blockade via PARP inhibitors. These repres...

BACKGROUND High-grade serous ovarian cancers are a distinct histological subtype of ovarian cancer often characterised by a dysfunctional BRCA/Fanconi anaemia (BRCA/FA) pathway, which is critical to the homologous recombination DNA repair machinery. An impaired BRCA/FA pathway sensitises tumours to the treatment with DNA cross-linking agents and to PARP inhibitors. The vast majority of inactiva...

Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a t...

PURPOSE/OBJECTIVES To investigate cancer surveillance behaviors of women at risk for hereditary breast and ovarian cancer (HBOC) who presented for clinical BRCA cancer susceptibility testing, specifically to describe cancer surveillance behaviors and reasons for not engaging in behaviors, compare surveillance behaviors with existing surveillance guidelines, and evaluate associations of cancer s...

Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The gene encoding the serine-threon...