GROWTH-REGULATION OF HUMAN BREAST AND OVARIAN TUMOR-CELLS BY HEREGULIN - EVIDENCE FOR THE REQUIREMENT OF ERBB2 AS A CRITICAL COMPONENT IN MEDIATING HEREGULIN RESPONSIVENESS

Alterations in the expression of the epidermal growth factor (EGF) rec eptor ErbB family are frequently encountered in a number of human canc ers. Two of these receptors, ErbB3 and ErbB4, are known to bind a fami ly of related proteins termed heregulins (HRGs) or neu differentiation factors. In biologically relevant systems, interaction of HRG with Er bB3 or ErbB4 results in the transactivation of ErbB2. In this report, we show that ErbB2 is a critical component in mediating HRG responsive ness in a panel of human breast and ovarian tumor cell lines. Because HRGs have been reported to elicit diverse biological effects on cultur ed cells, including growth stimulation, growth inhibition, and inducti on of differentiation, we systematically examined the effect of rHRG b eta 1 on tumor cell proliferation, HRG binding studies were performed with a panel of breast and ovarian tumor cell lines expressing a range of levels of ErbB2. The biological responses to HRG were also compare d to EGF and to the growth-inhibitory anti-ErbB2 antibody, 4D5. In mos t cases, HRG stimulation of DNA synthesis correlated with positive eff ects on cell cycle progression and cell number and with enhancement of colony formation in soft agar. On each cell line tested, the HRG effe cts were distinguishable from EGF and 4D5. Our findings indicate that HRG induces cell proliferation in a number of tumor cell lines. In add ition, we show that methods for measuring cell proliferation, as well as experimental conditions, are critical for determining HRGs effect o n tumor cell growth in vitro.