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.

Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy / Giuliano, Mario; Hu, H; Wang, Yc; Fu, X; Nardone, Agostina; Herrera, S; Mao, S; Contreras, A; Gutierrez, C; Wang, T; Hilsenbeck, Sg; DE ANGELIS, Carmine; Wang, Nj; Heiser, Lm; Gray, Jw; Lopez Tarruella, S; Pavlick, Ac; Trivedi, Mv; Chamness, Gc; Chang, Jc; Osborne, Ck; Rimawi, Mf; Schiff, R.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 21:17(2015), pp. 3995-4003. [10.1158/1078-0432]

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

GIULIANO, MARIO;DE ANGELIS, CARMINE;
2015

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: 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.
2015
Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy / Giuliano, Mario; Hu, H; Wang, Yc; Fu, X; Nardone, Agostina; Herrera, S; Mao, S; Contreras, A; Gutierrez, C; Wang, T; Hilsenbeck, Sg; DE ANGELIS, Carmine; Wang, Nj; Heiser, Lm; Gray, Jw; Lopez Tarruella, S; Pavlick, Ac; Trivedi, Mv; Chamness, Gc; Chang, Jc; Osborne, Ck; Rimawi, Mf; Schiff, R.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 21:17(2015), pp. 3995-4003. [10.1158/1078-0432]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/616074
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