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PgR-negative tumors have more aggressive features: they are larger, have more nodal<br />
metastases, are more likely to be aneuploid, and are more rapidly proliferating.<br />
Interestingly, PgR-negative tumors are also associated with a significantly higher<br />
frequency of H<strong>ER</strong>2 overexpression and high expression of EGFR. About 30% of <strong>ER</strong>-<br />
positive, PgR-negative tumors are H<strong>ER</strong>2- and/or EGFR-positive compared with only<br />
10% of <strong>ER</strong>-positive, PgR-positive tumors (147). As indicated in the preclinical setting,<br />
several recent clinical reports also suggest that high growth factor receptor activity may<br />
be associated with reduced PgR levels in breast cancer (148-151). For example,<br />
tamoxifen-treated women with <strong>ER</strong>-positive/PgR-negative, and either EGFR or H<strong>ER</strong>2-<br />
positive tumors, are found to have a significantly worse outcome than patients in the<br />
same subgroup whose tumors display low EGFR or H<strong>ER</strong>2. In contrast, deleterious<br />
effects of high EGFR or H<strong>ER</strong>2 are less apparent in patients with <strong>ER</strong>-positive/PgR-<br />
positive tumors (147) (figure 3). One possible explanation is that less active EGFR and<br />
H<strong>ER</strong>2 signaling despite receptor overexpression occurs in <strong>ER</strong>-positive/PgR-positive<br />
tumors and results in a smaller impact on response to tamoxifen. In this context, PgR<br />
loss may be a maker of active EGFR/H<strong>ER</strong>2 signaling networks in these H<strong>ER</strong>2-positive<br />
tumors.<br />
C. H<strong>ER</strong>2/<strong>ER</strong> crosstalk in acquired endocrine resistance<br />
Recent provocative clinical studies document that acquired resistance to tamoxifen may<br />
also be associated with an increase in H<strong>ER</strong>2 expression and/or gene amplification as<br />
shown in preclinical models. One study analyzed the changes in growth factor receptors<br />
and their associated downstream kinases in tumors after the development of tamoxifen<br />
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