ERBB-Receptors and Drug Response in Breast Cancer.
Annual rept. 15 Aug 97-14 Aug 98
GEORGETOWN UNIV WASHINGTON DC
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There is a compelling need for better ways to select cytotoxic therapy for a given patient with breast cancer The role of the members of the type 1 growth factor receptor family ErbB1-4 and their ligands in predicting response to chemotherapy is still unknown. We hypothesize that signaling through one or a combination of the FrbB receptors in breast cancer cells increases the activity of topoisomerase II alpha which then sensitizes cells to doxorubicin. During the time of this award we have shown that ErbB2 signaling has an effect on cell cycle distribution of the topo II alpha enzyme and its phosphorylation state, leading to increased sensitivity to doxorubicin but resistance to the alkylator cyclophosphamide. We have also made the novel discovery that topo II alpha is phosphorylated on tyrosine residues as opposed to serinethreonine as previously described. This effect is seen in response to ErbB2-mediatel signaling, but not ErbB3, and we believe that this phosphorylation event may be important to determining sensitivity to doxorubicin. We propose that the biology of the change in topo II alpha activity may be understood by global changes in DNA repair enzymes, brought about by signaling through the EGFR superfamily. This may also explain the resistance to alkylators seen in our system and the clinical setting.
- Medicine and Medical Research