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The Role of Growth Factor Receptor Pathways in Human Breast Cancer Cells Adapted to Long-term Estrogen Deprivation

Department of Pharmacology and Experimental Therapeutics, University of Maryland Baltimore, Baltimore, Maryland

Requests for reprints: Angela Brodie, Department of Pharmacology and Experimental Therapeutics, University of Maryland Baltimore, School of Medicine, Health Science Facility I, Room 580G, 685 W. Baltimore Street, Baltimore, MD 21201. Phone: 410-706-3137; Fax: 410-706-0032; E-mail: abrodie{at}umaryland.edu.

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.

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