ER ER ER ER - Endocrine Reviews

PgR-negative tumors have more aggressive features: they are larger, have more nodal
metastases, are more likely to be aneuploid, and are more rapidly proliferating.
Interestingly, PgR-negative tumors are also associated with a significantly higher
frequency of HER2 overexpression and high expression of EGFR. About 30% of ER-
positive, PgR-negative tumors are HER2- and/or EGFR-positive compared with only
10% of ER-positive, PgR-positive tumors (147). As indicated in the preclinical setting,
several recent clinical reports also suggest that high growth factor receptor activity may
be associated with reduced PgR levels in breast cancer (148-151). For example,
tamoxifen-treated women with ER-positive/PgR-negative, and either EGFR or HER2-
positive tumors, are found to have a significantly worse outcome than patients in the
same subgroup whose tumors display low EGFR or HER2. In contrast, deleterious
effects of high EGFR or HER2 are less apparent in patients with ER-positive/PgR-
positive tumors (147) (figure 3). One possible explanation is that less active EGFR and
HER2 signaling despite receptor overexpression occurs in ER-positive/PgR-positive
tumors and results in a smaller impact on response to tamoxifen. In this context, PgR
loss may be a maker of active EGFR/HER2 signaling networks in these HER2-positive
tumors.
C. HER2/ER crosstalk in acquired endocrine resistance
Recent provocative clinical studies document that acquired resistance to tamoxifen may
also be associated with an increase in HER2 expression and/or gene amplification as
shown in preclinical models. One study analyzed the changes in growth factor receptors
and their associated downstream kinases in tumors after the development of tamoxifen
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