INVOLVEMENT OF HEREGULIN-BETA-2 IN THE ACQUISITION OF THE HORMONE-INDEPENDENT PHENOTYPE OF BREAST-CANCER CELLS

The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast ca ncer is not yet known. The discovery of the growth factor heregulin (H RG) has allowed us to investigate a number of biological events that a re regulated by erbB-2, -3, and -4 signal transduction. To determine t he role of HRG in breast cancer tumor progression, we have developed a n in vitro/in vivo model. We transfected HRG cDNA into the estrogen re ceptor (ER)positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone-dependent to -independent phen otype. The biochemical and biological characteristics presented here d emonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation . MCF-7/heregulin-transfected cells, which express relatively high lev els of HRG, developed estrogen independence and resistance to antiestr ogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype, In contrast with control parental/wild- type cells, estradiol-mediated down regulation of erbB-2 expression is blocked completely in this particular model system. These results ind icate that HRG plap a role in the disruption of ER function. When a tr ansient transfection with an ERE-CAT construct was introduced into the se HRG-transfected MCF-7 cells, we observed that the ER was transcript ionally inactive. This suggests that ER signaling is altered in HRG-tr ansfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directl y related to the constitutive activation of the erbB-2, erbB-3, and er bB-4 receptor signaling cascade, The data presented here suggest a clo se cross-regulation between the erbB-2/4 receptors and ER and provide nem insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.