The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation

Gauri J. Sabnis, Danijela Jelovac, Brian Long, Angela Brodie

Research output: Contribution to journalArticle

Abstract

To study the long-term effects of estrogen deprivation on breast cancer, MCF-7Ca human estrogen receptor-positive breast cancer cells stably transfected with human aromatase gene were cultured in the steroid-depleted medium for 6 to 8 months until they had acquired the ability to grow. Proliferation of these cells (UMB-1Ca) was accompanied by increased expression of human epidermal growth factor receptor 2, increased activation of AKT through phosphorylation at Ser473 and Thr308, and increased invasion compared with parental MCF-7Ca cells. Estrogen receptor expression was also increased 5-fold. Although growth was inhibited by the antiestrogen fulvestrant, the IC50 was 100-fold higher than for parental MCF-7Ca cells. Aromatase inhibitor letrozole also inhibited growth at 10,000-fold higher concentration than required for MCF-7Ca cells, whereas anastrozole, exemestane, formestane, and tamoxifen were ineffective at 100 nmol/L. Growth of UMB-1Ca cells was inhibited by phosphatidylinositol 3-kinase inhibitor wortmannin (IC50 ∼25 nmol/L) and epidermal growth factor receptor kinase inhibitor gefitinib (ZD 1839; IC50 ∼10 μmol/L) whereas parental MCF-7Ca cells were insensitive to these agents. Concomitant treatment of UMB-1Ca cells with the signal transduction inhibitors and anastrozole and tamoxifen restored their growth inhibitory effects. These studies show that estrogen deprivation results in up-regulation of growth factor signaling pathways, which leads to a more aggressive and hormone refractory phenotype. Cross-talk between ER and growth factor signaling was evident as inhibition of these pathways could restore estrogen responsiveness to these cells.

Original languageEnglish (US)
Pages (from-to)3903-3910
Number of pages8
JournalCancer Research
Volume65
Issue number9
DOIs
StatePublished - May 1 2005
Externally publishedYes

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Growth Factor Receptors
Estrogens
Breast Neoplasms
Inhibitory Concentration 50
exemestane
letrozole
Tamoxifen
Growth
Estrogen Receptors
Intercellular Signaling Peptides and Proteins
Phosphatidylinositol 3-Kinase
Aromatase Inhibitors
Aromatase
Estrogen Receptor Modulators
Epidermal Growth Factor Receptor
Signal Transduction
Up-Regulation
Steroids
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation. / Sabnis, Gauri J.; Jelovac, Danijela; Long, Brian; Brodie, Angela.

In: Cancer Research, Vol. 65, No. 9, 01.05.2005, p. 3903-3910.

Research output: Contribution to journalArticle

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