Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy

Mario Giuliano, Huizhong Hu, Yen Chao Wang, Xiaoyong Fu, Agostina Nardone, Sabrina Herrera, Sufeng Mao, Alejandro Contreras, Carolina Gutierrez, Tao Wang, Susan G. Hilsenbeck, Carmine D. Angelis, Nicholas J. Wang, Laura M. Heiser, Joe W. Gray, Sara Lopez-Tarruella, Anne C. Pavlick, Meghana V. Trivedi, Gary C. Chamness, Jenny C. ChangC. Kent Osborne, Mothaffar F. Rimawi, Rachel Schiff

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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: ERP = 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.

Original languageEnglish (US)
Pages (from-to)3995-4003
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Giuliano, M., Hu, H., Wang, Y. C., Fu, X., Nardone, A., Herrera, S., Mao, S., Contreras, A., Gutierrez, C., Wang, T., Hilsenbeck, S. G., Angelis, C. D., Wang, N. J., Heiser, L. M., Gray, J. W., Lopez-Tarruella, S., Pavlick, A. C., Trivedi, M. V., Chamness, G. C., ... Schiff, R. (2015). Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy. Clinical Cancer Research, 21(17), 3995-4003. https://doi.org/10.1158/1078-0432.CCR-14-2728