A significant number of HER-2 amplified breast
cancers is effectively treated by
trastuzumab and further shows receptor-enhanced chemosensitivity. Recent studies have postulated transactivation of HER-2 also in
tumors expressing phosphorylated/activated HER-2 (pHER-2) and of the HER-3/HER-4
ligand heregulin (
HRG), independent of HER-2 amplification. As a consequence, a subset of
tumors without HER-2 overexpression would be sensitive to
trastuzumab chemotherapy. To investigate the potential transactivation of HER-2, in 171 breast
cancers from the GENICA study with negative/low expression of HER-2 we analyzed the expression of pHER-2,
HRG, HER-3 and HER-4 by immunohistochemistry. None of the
tumors examined displayed expression of pHER-2. Moderate or strong cytoplasmic staining of
HRG, HER-3 and HER-4 was observed in 44 (26%), 67 (39%) and 33 (19%) cases, respectively. No association of
HRG, HER-3 and HER-4 with the survival of patients or with known prognostic clinical factors was seen. In conclusion, our data obtained on a well-characterized cohort of breast
cancers provide no evidence of HER-2-activation in the absence of HER-2 overexpression. The
biological function and clinical implications of
HRG, HER-3 and HER-4 in this group of
tumors remain unclear. Our results cannot support the hypothesis of a transactivation of HER-2 and thus a possible therapeutic benefit of
trastuzumab in HER-2 negative breast
cancers.