Prognosis of hormone-dependent breast cancers: Implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet

Kasi McCune, Poornima Bhat-Nakshatri, Mangesh A. Thorat, Kenneth Nephew, Sunil Badve, Harikrishna Nakshatri

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Estrogen receptor α (ERα)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERα-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERα:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERα binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERα-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERα-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERα-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERα-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy.

Original languageEnglish
Pages (from-to)685-696
Number of pages12
JournalCancer Research
Volume70
Issue number2
DOIs
StatePublished - Jan 15 2010

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Gene Regulatory Networks
Immunologic Factors
Estrogen Receptors
Transcription Factors
Hormones
Insulin
Breast Neoplasms
MCF-7 Cells
Tamoxifen
Transcription Factor 3
Chromatin Immunoprecipitation
Extracellular Signal-Regulated MAP Kinases
Epidermal Growth Factor
Immune System
Intercellular Signaling Peptides and Proteins
Estrogens
Therapeutics
Biomarkers
Databases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Prognosis of hormone-dependent breast cancers: Implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet",
abstract = "Estrogen receptor α (ERα)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERα-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERα:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERα binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERα-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERα-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERα-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERα-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy.",
author = "Kasi McCune and Poornima Bhat-Nakshatri and Thorat, {Mangesh A.} and Kenneth Nephew and Sunil Badve and Harikrishna Nakshatri",
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T2 - Implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet

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AU - Bhat-Nakshatri, Poornima

AU - Thorat, Mangesh A.

AU - Nephew, Kenneth

AU - Badve, Sunil

AU - Nakshatri, Harikrishna

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