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Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments. [ABSTRACT FROM AUTHOR]

The ERBB2/HER2/NEU receptor tyrosine kinase gene is amplified in up to 30% of human breast cancers. The frequent and specific selection of this receptor kinase gene for amplification in breast cancer implies that it has important normal functions in the mammary gland. To investigate the functions of ErbB2 during normal mouse mammary gland development we transplanted mammary buds from genetically rescued ErbB2-/- embryos that express ErbB2 in the cardiac muscle. ErbB2-/- mammary buds transplanted to a wild-type mammary fat pad support outgrowth of an epithelial tree that advances only slowly through the mammary fat pad at puberty. This penetration defect is associated with structural defects in terminal end buds, characterized by a decrease in body cell number, an increased presence of cap-like cells in the prelumenal compartment, and the presence of large luminal spaces. Lobuloalveolar development was not affected in glands that developed from ErbB2-/- transplanted tissue. The results may have implications for the aggressive phenotypes associated with ERBB2-overexpressing mammary carcinomas. [ABSTRACT FROM AUTHOR]

NFBD1/MDC1 (mediator of DNA damage checkpoint 1) is a nuclear factor with an aminoterminal FHA (forkhead-associated) domain and a tandem repeat of BRCT (breast cancer susceptibility gene-1 carboxyl terminus) domains. We have previously shown that NFBD1 is an early participant in DNA damage signaling pathways and that ionizing radiation-induced nuclear foci (IRIF) of NFBD1 colocalize with several DNA checkpoint signaling and repair factors. We report here that NFBD1 physically associates with ATM, p53, components of the MRE11-RAD50-NBS1 (MRN) complex, and γ-H2AX. An overexpressed FHA domain-containing fragment of NFBD1 binds to endogenous NFBD1 and components of the MRN complex, but not to γ-H2AX. This fragment interferes with IRIF formation by endogenous NFBD1, MRE11, or NBS1. A BRCT domain-containing fragment of NFBD1 binds to γ-H2AX and 53BP1, but not to components of the MRN complex, and abolishes IRIF formation by NFBD1, MRE11, NBS1, 53BP1, CHK2 phospho-T68, γ-H2AX, and possible ATM/ATR substrates recognized by anti-phospho-SQ/TQ antibody. These results suggest that NFBD 1 is an ATM/ATR-dependent organizer that recruits DNA checkpoint signaling and repair proteins to the sites of DNA damage. [ABSTRACT FROM AUTHOR]

Overexpression of the receptor tyrosine kinase ErbB2/HER2/Neu (ErbB2) occurs in 15 – 40% of human breast cancers. To determine the function of ErbB2 signaling during normal mouse mammary gland development, we expressed a carboxyl-terminal truncated dominant negative allele of ErbB2 (ErbB2ΔIC) in the developing mouse mammary gland. Despite ErbB2ΔIC expression within mammary glands of pubescent virgin and pregnant mice, a phenotype was not observed until late in pregnancy. At 1 day post-partum, lactationally active, distended lobuloalveoli failed to form. This phenotype was exaggerated in multiparous females expressing ErbB2ΔIC. Immunohistochemical staining for ErbB2ΔIC revealed a concordance between high levels of ErbB2ΔIC protein expression and the absence of lactational products within the lumens of ErbB2ΔIC stained lobuloalveoli. These results demonstrate that ErbB2 signaling is required for proper mammary development and lactation at parturition. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have suggested that autocrine production of Neuregulin (NRG), a growth factor that activates members of the Epidermal Growth Factor Receptor/ErbB family of proto-oncogenes, is sufficient for breast tumor initiation and progression. To elucidate the molecular mechanisms regulating these events, we undertook a global analysis of genes regulated by NRG in luminal mammary epithelial cell lines. Gene expression profiling of estrogen receptor-positive T47D cells exposed to NRG-1 revealed both previously identified and novel targets of NRG activation. Profiling of other estrogen receptor-positive breast cancer cell lines, MCF7 and SUM44, yielded a group of twenty-one genes whose transcripts are upregulated by NRG in all three lines tested. The NRG targets are FBJ murine osteosarcoma viral oncogene homolog B, Early growth response 1, v-jun avian sarcoma virus 17 oncogene homolog, Activating transcription factor 3, Homo sapiens cDNA FLJ31636 fis, Jun B proto-oncogene, Forkhead box C1, Platelet/endothelial cell adhesion molecule 1, NADPH-dependent retinol dehydrogenase/reductase, Dual specificity phosphatase 5, NGF inducible protein TIS21, Connective tissue growth factor, Jun D proto-oncogene, Serum response factor, Cullin 1, v-myc avian myelocytomatosis viral oncogene, Transient receptor potential channel 1, Low density lipoprotein receptor, Transforming growth factor beta 1, Nucleoporin 88 kDa, and Pleckstrin homology-like domain A1. Since NRG activation of these cells induces resistance to anti-hormonal therapy, the identified genes may provide clues to molecular events regulating mammary tumor progression and hormone independence. [Copyright &y& Elsevier]