MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

X. Rao, G. Di Leva, M. Li, F. Fang, C. Devlin, C. Hartman-Frey, M. E. Burow, Mircea Ivan, C. M. Croce, Kenneth Nephew

Research output: Contribution to journalArticle

237 Citations (Scopus)

Abstract

Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of Β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-Β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two oncomirs may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.

Original languageEnglish
Pages (from-to)1082-1097
Number of pages16
JournalOncogene
Volume30
Issue number9
DOIs
StatePublished - Mar 3 2011

Fingerprint

MicroRNAs
Breast Neoplasms
Estrogen Receptors
Growth
fulvestrant
Hormone Antagonists
Cell Line
Catenins
Aromatase Inhibitors
Estrogen Receptor Modulators
MCF-7 Cells
Tamoxifen
Therapeutics
Transcriptome
Drug Resistance
Growth Hormone
Estradiol
Cell Cycle
Estrogens
Cell Death

Keywords

  • antiestrogen
  • breast cancer
  • drug resistance
  • fulvestrant
  • microRNAs

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. / Rao, X.; Di Leva, G.; Li, M.; Fang, F.; Devlin, C.; Hartman-Frey, C.; Burow, M. E.; Ivan, Mircea; Croce, C. M.; Nephew, Kenneth.

In: Oncogene, Vol. 30, No. 9, 03.03.2011, p. 1082-1097.

Research output: Contribution to journalArticle

Rao, X, Di Leva, G, Li, M, Fang, F, Devlin, C, Hartman-Frey, C, Burow, ME, Ivan, M, Croce, CM & Nephew, K 2011, 'MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways', Oncogene, vol. 30, no. 9, pp. 1082-1097. https://doi.org/10.1038/onc.2010.487
Rao, X. ; Di Leva, G. ; Li, M. ; Fang, F. ; Devlin, C. ; Hartman-Frey, C. ; Burow, M. E. ; Ivan, Mircea ; Croce, C. M. ; Nephew, Kenneth. / MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. In: Oncogene. 2011 ; Vol. 30, No. 9. pp. 1082-1097.
@article{c996cf69606b4bf8bb863cfdce0079b5,
title = "MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways",
abstract = "Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of Β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-Β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two oncomirs may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.",
keywords = "antiestrogen, breast cancer, drug resistance, fulvestrant, microRNAs",
author = "X. Rao and {Di Leva}, G. and M. Li and F. Fang and C. Devlin and C. Hartman-Frey and Burow, {M. E.} and Mircea Ivan and Croce, {C. M.} and Kenneth Nephew",
year = "2011",
month = "3",
day = "3",
doi = "10.1038/onc.2010.487",
language = "English",
volume = "30",
pages = "1082--1097",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

AU - Rao, X.

AU - Di Leva, G.

AU - Li, M.

AU - Fang, F.

AU - Devlin, C.

AU - Hartman-Frey, C.

AU - Burow, M. E.

AU - Ivan, Mircea

AU - Croce, C. M.

AU - Nephew, Kenneth

PY - 2011/3/3

Y1 - 2011/3/3

N2 - Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of Β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-Β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two oncomirs may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.

AB - Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of Β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-Β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two oncomirs may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.

KW - antiestrogen

KW - breast cancer

KW - drug resistance

KW - fulvestrant

KW - microRNAs

UR - http://www.scopus.com/inward/record.url?scp=79952281614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952281614&partnerID=8YFLogxK

U2 - 10.1038/onc.2010.487

DO - 10.1038/onc.2010.487

M3 - Article

C2 - 21057537

AN - SCOPUS:79952281614

VL - 30

SP - 1082

EP - 1097

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 9

ER -