Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 17, Pages 3995-4003Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-2728
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Funding
- Specialized Programs of Research Excellence (SPORE)
- Dan L. Duncan Cancer Center
- Human Tissue Acquisition and Pathology (HTAP) Shared Resource Grant from the National Cancer Institute [P30CA125123]
- Stand Up To Cancer Dream Team Translational Research Grant [SU2C-AACR-DT0409]
- Breast Cancer Research Foundation
- Entertainment Industry Foundation/Lee Jeans
- Cancer Prevention and Research Institute of Texas (CPRIT) program-Baylor College of Medicine Comprehensive Cancer Training Program [RP101499]
- GlaxoSmithKline
- [P50 CA58183]
- [CA 186784-01]
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Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER-) converted to ER+ upon anti-HER2 therapy. In ER-/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001). Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. (C)2015 AACR.
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