ER ER ER ER - Endocrine Reviews

esistance (92). A tissue microarray was constructed of pairs of samples from the same
patient, firstly at presentation and secondly at the development of tamoxifen resistance
during adjuvant therapy. A total of 39 patients had sufficient tissue in both samples on
the arrays to provide near-complete sets of data. Pretreatment, strong positive correlations
between ER, PgR, and Bcl-2, and an inverse correlation between ER and HER2 were
found, as expected. These correlations were lost in the tamoxifen resistant tumors and
replaced by strong correlations between ER and phosphorylated (p) p38 (p-p38) and
phosphorylated p42/44 MAPK (p-p42/44 MAPK). ER expression was lost in 17% of
resistant tumors. Three (11%) of the 26 tumors originally negative for HER2 became
amplified and/or overexpressed at resistance. All ER-positive tumors that overexpressed
HER2 originally or at resistance expressed high levels of p-p38. In the pretreatment and
tamoxifen-resistant specimens, there were strong correlations between p-p38 and p-
p42/44 MAPK. Therefore, the molecular pathways driving tumor growth can change as
the tumor progresses, and the HER family may play an important role in the development
of acquired tamoxifen resistance.
Acquired HER2 gene amplification during cancer progression after tamoxifen adjuvant
therapy has also been recently reported in patients’ circulating tumor cells (93). Similarly,
serum HER2 conversion from negative to positive has also been shown in patients with
advanced disease at the time of disease progression on endocrine therapy (152). These
data suggest that acquired HER2 overexpression can occur during endocrine treatment,
perhaps as an adaptive mechanism for tumor cell survival on these therapies or as a
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