This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sabnis, G. J. Articles by Brodie, A. Search for Related Content PubMed PubMed Citation Articles by Sabnis, G. J. Articles by Brodie, A.

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.

This article has been cited by other articles:

				J. Geisler, H. Helle, D. Ekse, N. K. Duong, D. B. Evans, Y. Nordbo, T. Aas, and P. E. Lonning Letrozole is Superior to Anastrozole in Suppressing Breast Cancer Tissue and Plasma Estrogen Levels Clin. Cancer Res., October 1, 2008; 14(19): 6330 - 6335. [Abstract] [Full Text] [PDF]

				G. J. Sabnis, L. F. Macedo, O. Goloubeva, A. Schayowitz, and A. M.H. Brodie Stopping Treatment Can Reverse Acquired Resistance to Letrozole Cancer Res., June 15, 2008; 68(12): 4518 - 4524. [Abstract] [Full Text] [PDF]

				S. Masri, S. Phung, X. Wang, X. Wu, Y.-C. Yuan, L. Wagman, and S. Chen Genome-Wide Analysis of Aromatase Inhibitor-Resistant, Tamoxifen-Resistant, and Long-Term Estrogen-Deprived Cells Reveals a Role for Estrogen Receptor Cancer Res., June 15, 2008; 68(12): 4910 - 4918. [Abstract] [Full Text] [PDF]

				L. F. Macedo, G. J. Sabnis, O. G. Goloubeva, and A. Brodie Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model Cancer Res., May 1, 2008; 68(9): 3516 - 3522. [Abstract] [Full Text] [PDF]

				V. C. Jordan and B. W. O'Malley Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer J. Clin. Oncol., December 20, 2007; 25(36): 5815 - 5824. [Abstract] [Full Text] [PDF]

				J. E Burdette and T. K Woodruff Activin and estrogen crosstalk regulates transcription in human breast cancer cells Endocr. Relat. Cancer, September 1, 2007; 14(3): 679 - 689. [Abstract] [Full Text] [PDF]

				G. Arpino, C. Gutierrez, H. Weiss, M. Rimawi, S. Massarweh, L. Bharwani, S. De Placido, C. K. Osborne, and R. Schiff Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy J Natl Cancer Inst, May 2, 2007; 99(9): 694 - 705. [Abstract] [Full Text] [PDF]

				G. Sabnis, O. Goloubeva, D. Jelovac, A. Schayowitz, and A. Brodie Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway Improves Response of Long-term Estrogen-Deprived Breast Cancer Xenografts to Antiestrogens Clin. Cancer Res., May 1, 2007; 13(9): 2751 - 2757. [Abstract] [Full Text] [PDF]

				N. Vasudevan and D. W. Pfaff Membrane-Initiated Actions of Estrogens in Neuroendocrinology: Emerging Principles Endocr. Rev., February 1, 2007; 28(1): 1 - 19. [Abstract] [Full Text] [PDF]

				A. Belosay, A. M.H. Brodie, and V. C.O. Njar Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells Cancer Res., December 1, 2006; 66(23): 11485 - 11493. [Abstract] [Full Text] [PDF]

				F Labrie Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA. Endocr. Relat. Cancer, June 1, 2006; 13(2): 335 - 355. [Abstract] [Full Text] [PDF]