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findings suggest that enhanced growth factor signaling, which upregulates both the<br />
genomic and non-genomic activities of <strong>ER</strong>, is a key contributor to the mechanism of<br />
acquired resistance to tamoxifen.<br />
Enhanced expression of EGFR and H<strong>ER</strong>2, together with subsequent downstream<br />
activation of signaling pathways regulated by p42/44 MAPK, has also been identified in<br />
breast cancer cell models that have become resistant over time to estrogen depletion or to<br />
AI therapy (99-101). Interestingly, MCF-7 cells adapted to grow in the presence of the<br />
potent antiestrogen fulvestrant also show increased EGFR signaling, suggesting that<br />
growth factor receptors play central roles in resistance to various endocrine therapies<br />
such as AIs and pure <strong>ER</strong> antagonists in addition to tamoxifen (94, 102, 103).<br />
III. The H<strong>ER</strong> tyrosine kinase receptor family and its role in the development of<br />
endocrine resistance -- Clinical evidence<br />
A. De novo endocrine resistance<br />
Cumulative clinical data suggest that patients with H<strong>ER</strong>2 and EGFR overexpressing<br />
tumors have a poorer outcome when treated with tamoxifen (13, 104, 105). In a subset of<br />
patients with metastatic breast cancer, results of published studies have been somewhat<br />
inconsistent due to different study designs, different techniques for measuring H<strong>ER</strong>2, and<br />
the relatively small numbers of patients included in each study. Despite this<br />
heterogeneity, a recently published meta-analysis examining the interaction between<br />
H<strong>ER</strong>2 expression and response to endocrine treatment in metastatic disease clearly shows<br />
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