ER ER ER ER - Endocrine Reviews

(Iressa), which can block signaling from EGFR/HER2 heterodimers, suggesting that
EGFR/HER2 signaling is directly involved in the growth-promoting activity of tamoxifen
in HER2-overexpressing cells. In this respect, gefitinib was highly effective in inhibiting
the tamoxifen-induced growth of MCF-7/HER2-18 cells, whereas it had only a modest
effect on estrogen-induced growth (14). The above mentioned findings are in agreement
with the clinical observations noted earlier indicating that tumors that co-express HER2
and AIB1 have poor outcome when treated with tamoxifen (12, 46).
C. HER2/ER crosstalk in acquired endocrine resistance models
Recent laboratory and clinical studies have shown that acquired resistance to tamoxifen
in tumors that originally express low levels of EGFR and HER2, is also associated with
increased EGFR/HER2 signaling including HER2 gene amplification (92, 93).
Experimental evidence by Nicholson and Gee’s group has demonstrated that
EGFR/HER2 signaling is involved in acquired tamoxifen resistance of breast cancer cells
in long term culture (94). These cells show increased levels of expression of EGFR and
HER2, increased activation of EGFR/HER2 heterodimers, and increased phosphorylation
of p42/44 MAPK, AKT, and nuclear ER on serine residues 118 and 167 (95, 96). As in
the de novo experimental models of tamoxifen resistance, the growth of these cells after
acquiring resistance, is significantly inhibited by treatment with the EGFR/HER2
inhibitors gefitinib or the monoclonal antiHER2 antibody trastuzumab (Herceptin) (96,
97). Another tyrosine kinase receptor, the IGF1R, has also been associated with
tamoxifen resistance. In fact, it has recently been reported that IGF-II treatment activates
both IGF1R and EGFR/HER2 in tamoxifen-resistant cells (98). Taken together, these
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