ER ER ER ER - Endocrine Reviews

Aromatase inhibitors (AIs) are a class of drugs that inhibit the enzyme aromatase, which
is responsible for converting androgens (produced by women in the adrenal glands) to
estrogen, thereby lowering the circulating, and perhaps the tumor levels, of estrogen. By
depriving ER of its estrogen ligand (4-6), AIs inhibit tumor growth and are proving
superior to tamoxifen at least in certain patient subsets (2, 7-9). However, the response
rate to these compounds is only slightly higher than the response rate to tamoxifen in
patients with advanced breast cancer, and both de novo (i.e. immediate) and acquired
resistance after an initial response commonly occur.
The membrane tyrosine kinase HER2 (c-ErbB2, HER2/neu) is gene-amplified in 20-25%
of ER-positive breast cancer (10). There is clinical evidence that tamoxifen is less
effective in HER2-positive tumors (11-13). Furthermore, preclinical models show that
HER2 overexpression can cause tamoxifen-stimulated growth as a mechanism of de novo
resistance (14-17) and that the HER family receptors are also implicated in acquired
resistance to this drug (18). Advanced studies of ER biology have revealed new insights
into ER action in breast cancer and have highlighted the role of an intimate cross-talk
between the ER and the Epidermal growth factor receptor (EGFR/HER1)/HER2
signaling pathways as a fundamental contributor to the development of resistance to
endocrine therapies (19-21).
Accumulating knowledge of the mechanisms by which breast cancer cells become
resistant to endocrine therapy, coupled with the availability of new compounds that can
interfere with the growth factor-driven signaling pathways involved in resistance to
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