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Hava Avraham, PhD

Associate Professor, Department of Medicine, Harvard Medical School

Scientist, Hematology/Oncology, Beth Israel Deaconess Medical Center

Contact Info

Hava Avraham
Beth Israel Deaconess Medical Center
4 Blackfan Circle
Boston, MA, 02115
Mailstop: Harvard Institutes of Medicine 322
Phone: 617-667-0073
Fax: 671-975-6373


Not Available.

DF/HCC Program Affiliation

Breast Cancer

Research Abstract

Our long term interest is to elucidate the molecular events involved in the genesis of breast cancer. Substantial evidence exists supporting direct roles for ErbB-2/neu and Src tyrosine kinase activation in breast cancer. CHK (Csk Homologous Kinase) is a cytoplasmic protein tyrosine kinase that phosphorylates and negatively regulates Src kinase activity. CHK is highly restricted in its expression and normally found in brain and hematopoietic cells. Our recent studies reveal that CHK expression was observed in 70 out of 80 primary breast cancer specimens, but not in normal breast tissues (0/19). Confocal microscopy analysis revealed co-localization of CHK with ErbB-2 and Src in these primary specimens (6/6). Furthermore, we observed that CHK participates in signaling in breast cancer cells by associating, via its SH2 domain, with ErbB-2 following heregulin stimulation. This association appears to be receptor specific (ErbB-2) and ligand specific (heregulin). Site-directed mutagenesis and phosphopeptide inhibition experiments indicated that CHK-SH2 binds to Tyr1253 of the rodent ErbB-2 (neu) or to Tyr1248 of the human ErbB-2. Moreover, CHK was able to downregulate ErbB-2/neu-activated Src kinases. Overexpression of CHK in MCF-7 breast cancer cells markedly inhibited cell growth and proliferative response to heregulin as well as decreased colony formation in soft agar. We aim to further assess the expression of CHK, relative to Src and ErbB-2 tyrosine kinases, in human breast tumors resected at various stages of malignant progression, and to determine the molecular and functional analyses of CHK-ErbB-2 and CHK pp60Src interactions in breast cancer cells. In addition, we aim to characterize the biological role(s) of CHK in breast cancer cellular responses and cell growth and to identify and characterize signaling molecules that associate with CHK in breast cancer cells.

Another interest involved functional characterization of a novel BRCA2-locus gene, AER, in breast cancer. Recent observations in our laboratory have indicated that the cytoplasmic tyrosine kinase RAFTK, which was originally cloned in our laboratory, interacts with a novel protein, as demonstrated by the yeast two-hybrid system and confirmed by a biochemical approach. We have termed this novel protein AER. This protein bears homology to the product of BRCA2's transcription unit, CG003. The overall goal is to investigate the function(s) of the AER protein in breast cancer cells.

A recent interest in our group is to elucidate the biological function of BRCA1. Our recent studies showed that heregulin stimulation induced the phosphorylation of BRCA1 activation and the serine/threonine kinase, AKT, in T47D human breast cancer cells. The heregulin-induced phosphorylation of BRCA1 was abrogated by PI3-K inhibitors and by a dominant-negative AKT. Furthermore, in the absence of heregulin, the ectopic expression of the constitutively active p110 subunit of PI3-K was sufficient to induce BRCA1 phosphorylation. This is a novel signaling pathway by which heregulin regulates BRCA1, and that BRCA1 phosphorylation is mediated by the PI3-K/AKT pathway upon heregulin stimulation of breast cancer cells. We aim to examine BRCA1 function and regulation in breast cancer. Since our observations indicate that BRCA1 phosphorylation is mediated by PI3-K/AKT and since PTEN and ECM were reported to regulate PI3-K/AKT signaling, we aim to characterize the biological function of BRCA1 and the role of PTEN and ECM in regulating BRCA1 activation and function.


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