No more than Ϸ30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.DNA repair ͉ FANCN ͉ Fanconi anemia ͉ hereditary predisposition T he presence of a family history is the most important predisposing factor for development of breast cancer. Among the genes known to be linked to familial breast cancer, BRCA1, BRCA2, CHK2, TP53, and ATM all participate in DNA damage responses (1), suggesting that familial breast cancer is, at least partly, a consequence of impaired genome stability control. PALB2 is a recently identified BRCA2-interacting protein, and a high fraction of each protein interacts with the other (2). Their association is essential for BRCA2 anchorage to nuclear structures and for its function in double strand break repair (DSBR) by homologous recombination (HR). Furthermore, introduction of PALB2 siRNAs sensitized cells to mitomycin C like BRCA2 siRNA (2). PALB2-depleted cells, therefore, display a Fanconi anemia (FA)/ BRCA2-deficient phenotype (3).Recent evidence shows that PALB2 is, in fact, another FA gene (known as FANCN), and that FANCN disease resembles FA arising from biallelic BRCA2 mutations in that the affected children are prone to develop embryonal tumors (medulloblastoma, Wilms tumor) and experience early bone marrow failure (4, 5). In other respects, FA-N cases have a typical FA phenotype. Their cells reveal increased chromosome breakage after interstrand cross-linking agent exposure, and these patients reveal growth retardation and various congenital malformations (4, 5). It is unclear why a different cancer predisposition phenotype exists in FA c...

The clinical use of trastuzumab (Herceptin), a humanized antibody against the HER2 growth factor receptor, has improved survival in patients with breast tumors with ERBB2 amplification and/or over-expression. However, most patients with advanced ERBB2 amplified breast cancers whose tumors initially respond to trastuzumab develop resistance to the drug, leading to tumor progression. To identify factors responsible for acquired resistance to trastuzumab, gene expression profiling was performed on subclones of an ERBB2 amplified breast cancer cell line, BT474, which had acquired resistance to trastuzumab. The most overexpressed gene in these subclones was PPP1R1B, encoding the DARPP-32 phosphatase inhibitor. Western analysis revealed that only the truncated isoform of the DARPP-32 protein, t-Darpp, was overexpressed in the trastuzumab resistant cells. Using gene silencing experiments, we confirmed that t-Darpp over-expression was required for trastuzumab resistance in these cells. Furthermore, transfecting t-Darpp in parental BT-474 cells conferred resistance to trastuzumab, suggesting that t-Darpp expression was sufficient for trastuzumab resistance. We also found that t-Darpp over-expression was associated with Akt activation and that the T75 residue in t-Darpp was required for both Akt activation and trastuzumab resistance. Finally, we found that full-length DARPP-32 and t-Darpp are expressed in a majority of primary breast tumors. Over-expression of full-length DARPP-32 can also confer resistance to trastuzumab and, moreover, is associated with a poor prognostic value in breast cancers. Thus, t-Darpp and DARPP-32 expression are novel prognostic and predictive biomarkers in breast cancer.

Registry of this type; over 37 724 individuals have been enrolled to date. One activity of this Registry is the semicentralized pathologic review of tumors from all probands. Given the semicentralized nature of the review, this study was undertaken to determine the reproducibility, source(s) of classification discrepancies and stratagems to circumvent discrepancies for histologic subtyping and grading of invasive breast cancer among the reviewing pathologists. A total of 13 pathologists reviewed 35 invasive breast cancers and classified them by primary and secondary histologic type, Nottingham grade and score. Lymph-vascular space invasion, circumscribed margins, syncytial growth and lymphocytic infiltrate were also evaluated. A training session using a separate set of slides was conducted prior to the study. General agreement, in terms of categoryspecific j's and percent agreement, and accuracy of classification relative to a reference standard were determined. Classification of histologic subtype was most consistent (and accurate) for mucinous carcinoma (j ¼ 1.0), followed by tubular (j ¼ 0.8) and lobular subtypes (j ¼ 0.8). Classification of medullary subtype was moderate (j ¼ 0.4), but additional evaluation of degree of lymphocytic infiltrate, syncytial growth and circumscribed margins identified most cases. Category-specific j's were moderate to good for Nottingham grade (j ¼ 0.5-0.7), with the greatest agreement obtained in categorizing grade I (j ¼ 0.7), and grade III tumors (j ¼ 0.7). A flexible classification strategy that employs individual and combined criteria provides good interobserver agreement for invasive breast cancers with uniform, unambiguous histology and compensates for classification discrepancies in the more histologically ambiguous or heterogeneous cancers. Keywords: interobserver reproducibility; invasive breast cancer; familial breast cancer; breast/ovarian cancer family registryThe reproducibility of the classification and grading of invasive breast cancer and the cause(s) of interobserver disagreement among pathologists have not been adequately evaluated. Prior studies evaluating interobserver concordance in categorizing breast lesions have documented improved diagnostic agreement when the pathologists involved used agreed-upon criteria, 1 but other potential sources of poor interobserver agreement, such as the difficulties in the application of the individual histologic criteria, the individual pathologist's variation in use of these criteria, and most importantly, the ambiguous or borderline and heterogeneous nature of the

The chemokine stromal cell-derived factor-1 (SDF-1) may function to attract CXCR4-expressing cancer cells to metastatic organs. We have previously demonstrated that low plasma SDF-1, a host-derived marker, increases distant metastatic risk in breast cancer. We therefore hypothesized that tumors overexpressing the SDF-1 receptor CXCR4 have an enhanced ability to metastasize in patients with low plasma SDF-1 levels. In this study, we determined the prognostic significance of activated CXCR4, or phosphorylated CXCR4 (p-CXCR4), and CXCR7, another receptor for SDF-1. Immunohistochemistry was performed on a tissue microarray built using 237 samples from the same cohort of patients for which we measured plasma SDF-1 levels. We found that the prognostic value of p-CXCR4 expression (hazard ratio or HR, 3.95; P ‫؍‬ 0.004) was superior to total CXCR4 expression (HR, 3.20; P ‫؍‬ 0.03). The rate of breast cancer-specific mortality was much higher in patients with both high p-CXCR4 expression and low plasma SDF-1 levels (HR, 5.96; P < 0.001) than either low plasma SDF-1 (HR, 3.59; P ‫؍‬ 0.01) or high p-CXCR4