Much of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in the BRCA1 tumour-suppressor gene. The nuclear protein BRCA1 has the properties of a transcription factor, and can interact with the recombination and repair protein RAD51. Young women with germline alterations in BRCA1 develop breast cancer at rates 100-fold higher than the general population, and BRCA1-null mice die before day 8 of development. However, the mechanisms of BRCA1-mediated growth regulation and tumour suppression remain unknown. Here we show that BRCA1 transactivates expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in a p53-independent manner, and that BRCA1 inhibits cell-cycle progression into the S-phase following its transfection into human cancer cells. BRCA1 does not inhibit S-phase progression in p21-/- cells, unlike p21+/+ cells, and tumour-associated, transactivation-deficient mutants of BRCA1 are defective in both transactivation of p21 and cell-cycle inhibition. These data suggest that one mechanism by which BRCA1 contributes to cell-cycle arrest and growth suppression is through the induction of p21.

INTRODUCTORY PARAGRAPHTo identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (N=10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in thirteen replication studies (N=27,591). Rs900400 near LEKR1 and CCNL1 (P=2×10−35), and rs9883204 in ADCY5 (P=7×10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and type 2 diabetes susceptibility,1 providing evidence that the well described association between lower birth weight and subsequent type 2 diabetes2,3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, the 9% of Europeans with 4 birth weight-lowering alleles were, on average, 113g (95%CI 89-137g) lighter at birth than the 24% with 0 or 1 allele (Ptrend=7×10−30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.4

2C4 (Pertuzumab, Omnitarg) is a monoclonal antibody targeting p185 her2/neu , which is overexpressed in 30% of invasive breast cancer. 2C4 is currently in phase II clinical trials for several types of cancers. This antibody has been reported to disrupt the association between p185 her2/neu and ErbB3. In our studies of epidermal growth factor receptor (EGFR)-p185 her2/neu heterodimerization, we noted that 2C4 formed associations with the EGFR-p185 her2/neu receptor complex. Our data argue against 2C4 as a universal heterodimerization blocker for p185 her2/neu , but indicate that cocktails of monoclonal antibodies binding distinct interaction surfaces of p185 her2/neu will emerge as the most potent targeted therapy. Oncogene (2008) 27, 3870-3874; doi:10.1038/onc.2008 published online 11 February 2008 Keywords: her2; Pertuzumab; heterodimer; 4D5 p185 her2/neu (Neu, c-ErbB2), a protein product related to the oncogene neu and the second member of the ErbB family of receptor tyrosine kinases, is overexpressed in many breast and ovarian cancers (van de Vijver et al., 1987;Slamon et al., 1989), early breast tumors (Lodato et al., 1990), gastrointestinal tumors (Cohen et al., 1989, lung tumors (Kern et al., 1990) as well as tumors of the pancreas (Williams et al., 1991). Extensive studies have shown that p185 her2/neu , acting as the preferred co-receptor for other family members, plays a dominant role in mediating the malignant phenotype Kokai et al., 1989;Lodato et al., 1990). p185 her2/neu -targeted therapy was initiated more than 20 years ago when monoclonal antibodies were used to reverse the malignant phenotype (Drebin et al., 1984(Drebin et al., , 1985. Since then, significant efforts have been spent to improve antibodies disabling p185 her2/neu . The humanized antibody 'trastuzumab' (rhumAb 4D5 or Herceptin) (Carter et al., 1992) is already used to treat advanced breast cancer and, more recently, as an adjuvant to prevent tumor emergence (Katsumata et al., 1995;Romond et al., 2005).2C4 (Pertuzumab, Omnitarg) is a distinct recombinant humanized monoclonal antibody targeting a different epitope on the extracellular domain of the p185 her2/neu receptor. Agus et al. (2002) suggested that 2C4 disrupts the association of p185 her2/neu with all other ErbB family receptors. This hypothesis was based on the 2C4 influence on p185 her2/neu -ErbB3 association.We first identified homodimers of p185 her2/neu and heterodimers of epidermal growth factor receptor (EGFR) with p185 her2/neu some years ago (Wada et al., 1990b). Moreover, we have defined interface binding molecules that do interfere with all heteromeric associations of the ErbB family (Berezov et al., 2002). In this study, we sought to investigate the effect of 2C4 preincubation on heteromeric EGFRp185 her2/neu interactions. Here, 'preincubation' refers to contacting cells on tissue culture plate with the antibody. Cells were washed twice with phosphate-buffered saline (PBS) before they were lysed to release membrane and cytoplasmic proteins.Experiments were pe...