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 Heiser, Joe 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

39 Citations (Scopus)

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

Fingerprint

Estrogen Receptors
Cell Survival
Up-Regulation
Breast Neoplasms
Therapeutics
Neoplasms
Heterografts
Therapeutic Uses
Epidermal Growth Factor Receptor
Estrogens
Research Design
Western Blotting
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy. / Giuliano, Mario; Hu, Huizhong; Wang, Yen Chao; Fu, Xiaoyong; Nardone, Agostina; Herrera, Sabrina; Mao, Sufeng; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Hilsenbeck, Susan G.; Angelis, Carmine D.; Wang, Nicholas J.; Heiser, Laura; Gray, Joe; Lopez-Tarruella, Sara; Pavlick, Anne C.; Trivedi, Meghana V.; Chamness, Gary C.; Chang, Jenny C.; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel.

In: Clinical Cancer Research, Vol. 21, No. 17, 01.09.2015, p. 3995-4003.

Research output: Contribution to journalArticle

Giuliano, M, Hu, H, Wang, YC, Fu, X, Nardone, A, Herrera, S, Mao, S, Contreras, A, Gutierrez, C, Wang, T, Hilsenbeck, SG, Angelis, CD, Wang, NJ, Heiser, L, Gray, J, Lopez-Tarruella, S, Pavlick, AC, Trivedi, MV, Chamness, GC, Chang, JC, Osborne, CK, Rimawi, MF & 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, vol. 21, no. 17, pp. 3995-4003. https://doi.org/10.1158/1078-0432.CCR-14-2728
Giuliano, Mario ; Hu, Huizhong ; Wang, Yen Chao ; Fu, Xiaoyong ; Nardone, Agostina ; Herrera, Sabrina ; Mao, Sufeng ; Contreras, Alejandro ; Gutierrez, Carolina ; Wang, Tao ; Hilsenbeck, Susan G. ; Angelis, Carmine D. ; Wang, Nicholas J. ; Heiser, Laura ; Gray, Joe ; Lopez-Tarruella, Sara ; Pavlick, Anne C. ; Trivedi, Meghana V. ; Chamness, Gary C. ; Chang, Jenny C. ; Osborne, C. Kent ; Rimawi, Mothaffar F. ; Schiff, Rachel. / Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 17. pp. 3995-4003.
@article{6214519d9b9247d1bba8426fc7812d95,
title = "Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy",
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.",
author = "Mario Giuliano and Huizhong Hu and Wang, {Yen Chao} and Xiaoyong Fu and Agostina Nardone and Sabrina Herrera and Sufeng Mao and Alejandro Contreras and Carolina Gutierrez and Tao Wang and Hilsenbeck, {Susan G.} and Angelis, {Carmine D.} and Wang, {Nicholas J.} and Laura Heiser and Joe Gray and Sara Lopez-Tarruella and Pavlick, {Anne C.} and Trivedi, {Meghana V.} and Chamness, {Gary C.} and Chang, {Jenny C.} and Osborne, {C. Kent} and Rimawi, {Mothaffar F.} and Rachel Schiff",
year = "2015",
month = "9",
day = "1",
doi = "10.1158/1078-0432.CCR-14-2728",
language = "English (US)",
volume = "21",
pages = "3995--4003",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with Anti-HER2 therapy

AU - Giuliano, Mario

AU - Hu, Huizhong

AU - Wang, Yen Chao

AU - Fu, Xiaoyong

AU - Nardone, Agostina

AU - Herrera, Sabrina

AU - Mao, Sufeng

AU - Contreras, Alejandro

AU - Gutierrez, Carolina

AU - Wang, Tao

AU - Hilsenbeck, Susan G.

AU - Angelis, Carmine D.

AU - Wang, Nicholas J.

AU - Heiser, Laura

AU - Gray, Joe

AU - Lopez-Tarruella, Sara

AU - Pavlick, Anne C.

AU - Trivedi, Meghana V.

AU - Chamness, Gary C.

AU - Chang, Jenny C.

AU - Osborne, C. Kent

AU - Rimawi, Mothaffar F.

AU - Schiff, Rachel

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84942859248&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942859248&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-14-2728

DO - 10.1158/1078-0432.CCR-14-2728

M3 - Article

C2 - 26015514

AN - SCOPUS:84942859248

VL - 21

SP - 3995

EP - 4003

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -