THE SIGNIFICANCE OF HEREGULIN IN BREAST-CANCER TUMOR PROGRESSION AND DRUG-RESISTANCE

The erbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in bre ast cancer patients. While evidence accumulates to support the relatio nship between erbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) of erbB -2 overexpression remains elusive. The discovery of heregulin has allo wed us to identify a number of related but distinct biological endpoin ts which appear responsive to signal transduction through the erbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiatio n have clear implications for the emergence, maintenance, and/or contr ol of malignancy, and represent established endpoints in the assessmen t of malignant progression in human breast cancer. Preliminary studies in vitro have shown that heregulin induces a biphasic growth effect o n cells with erbB-2 overexpression. Interestingly, we observed that ex pression of heregulin correlates with a more aggressive/invasive, vime ntin-positive phenotype in breast cancer cells lines. Therefore, we ha ve postulated that heregulin is involved in breast cancer tumor progre ssion. We have shown that heregulin induces in vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage d ependent and independent manner. Interestingly, a heregulin neutralizi ng antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engine ered cells which constitutively express heregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenoty pe. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifen in vitro and in vivo, and moreov er these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lost bcl-2 expression as compared with the contr ol tumors. In addition, presumably by activation/regulation of topoiso merase II, the heregulin-transfected cells become exquisitely sensitiv e to doxorubicin and VP-16. Clearly, mechanistic aspects of the erbB-2 /4 and heregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic tr eatments for certain patients, or improve treatment regimens for a lar ge number of women. The study of heregulin and its co-expression with erbB-2/4 receptor and the assessment of its involvement in the progres sion from the in situ stage of breast tumors to the invasive one will additionally increase the relevance of heregulin as a prognostic/diagn ostic factor. We believe that our studies provide new insights into br east cancer diagnosis, prognosis, and treatment.