ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms

Hirokazu Kurokawa, Carlos L. Arteaga

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

It has been reported that overexpression of the epidermal growth factor receptor (erbB1) or its homologous receptor, HER2 (erbB2), can confer antiestrogen resistance to estrogen receptor (ER)-positive human breast cancer cells. Aberrant signaling by receptors of the erbB network up-regulates a number of signaling pathways, which include phospholipase C-γ1, Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase, phosphatidylinositol 3′-kinase and its target, the serine/threonine kinase Akt, stress-activated protein kinases, signal transducers and activators of transcription, and c-Jun-NH2-terminal kinase (JNK). Akt has been reported to induce estrogen-independent transcription of ER. Here we show that transfection of ER-positive, HER2 gene-amplified BT-74 cells with an expression vector encoding dominant-negative (K179M) Akt1 partially restored the ability of tamoxifen to inhibit estradiol-stimulated ER reporter activity. Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture. Data will be presented to suggest that, in addition to mitogen-activated protein kinase, Akt is an important mediator of HER2-mediated antiestrogen resistance in human breast cancer cells.

Original languageEnglish (US)
JournalClinical Cancer Research
Volume9
Issue number1 II
StatePublished - Jan 1 2003

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Estrogen Receptor Modulators
Estrogen Receptors
Breast Neoplasms
Tamoxifen
Estradiol
Phosphatidylinositol 3-Kinase
erbB-2 Genes
MAP Kinase Kinase Kinases
JNK Mitogen-Activated Protein Kinases
Protein-Serine-Threonine Kinases
Extracellular Signal-Regulated MAP Kinases
MCF-7 Cells
Type C Phospholipases
Heat-Shock Proteins
Mitogen-Activated Protein Kinases
Transducers
Mitogens
Epidermal Growth Factor Receptor
Adenoviridae
Protein Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. / Kurokawa, Hirokazu; Arteaga, Carlos L.

In: Clinical Cancer Research, Vol. 9, No. 1 II, 01.01.2003.

Research output: Contribution to journalArticle

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