Tamoxifen is the most commonly prescribed therapy for patients with estrogen 
receptor (ER)α-positive breast tumors. Tumor resistance to tamoxifen remains a 
serious clinical problem especially in patients with tumors that also 
overexpress human epidermal growth factor receptor 2 (HER2). Current preclinical 
models of HER2 overexpression fail to recapitulate the clinical spectrum of 
endocrine resistance associated with HER2/ER-positive tumors. Here, we show that 
ectopic expression of a clinically important oncogenic isoform of HER2, HER2Δ16, 
which is expressed in >30% of ER-positive breast tumors, promotes tamoxifen 
resistance and estrogen independence of MCF-7 xenografts. MCF-7/HER2Δ16 cells 
evade tamoxifen through upregulation of BCL-2, whereas mediated suppression of 
BCL-2 expression or treatment of MCF-7/HER2Δ16 cells with the BCL-2 family 
pharmacological inhibitor ABT-737 restores tamoxifen sensitivity. 
Tamoxifen-resistant MCF-7/HER2Δ16 cells upregulate BCL-2 protein levels in 
response to suppressed ERα signaling mediated by estrogen withdrawal, tamoxifen 
treatment or fulvestrant treatment. In addition, HER2Δ16 expression results in 
suppression of BCL-2-targeting microRNAs miR-15a and miR-16. Reintroduction of 
miR-15a/16 reduced tamoxifen-induced BCL-2 expression and sensitized 
MCF-7/HER2Δ16 to tamoxifen. Conversely, inhibition of miR-15a/16 in 
tamoxifen-sensitive cells activated BCL-2 expression and promoted tamoxifen 
resistance. Our results suggest that HER2Δ16 expression promotes 
endocrine-resistant HER2/ERα-positive breast tumors and in contrast to wild-type 
HER2, preclinical models of HER2Δ16 overexpression recapitulate multiple 
phenotypes of endocrine-resistant human breast tumors. The mechanism of HER2Δ16 
therapeutic evasion, involving tamoxifen-induced upregulation of BCL-2 and 
suppression of miR-15a/16, provides a template for unique therapeutic 
interventions combining tamoxifen with modulation of microRNAs and/or 
ABT-737-mediated BCL-2 inhibition and apoptosis.