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