This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-08-0857v1 69/4/1416    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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. Articles by Brodie, A. Search for Related Content PubMed PubMed Citation Articles by Sabnis, G. Articles by Brodie, A.

Trastuzumab Reverses Letrozole Resistance and Amplifies the Sensitivity of Breast Cancer Cells to Estrogen

¹ Department of Pharmacology and Experimental Therapeutics, University of Maryland Baltimore; ² University of Maryland Greenebaum Cancer Center, Baltimore, Maryland

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

Key Words: aromatase inhibitors • estrogen • trastuzumab • ER • Her-2 • breast cancer

In this study, we investigated adaptive mechanisms associated with aromatase inhibitor (AI) resistance in breast cancer cells and show that sensitivity to AIs can be extended through dual inhibition of estrogen receptor (ER) and human epidermal receptor-2 (Her-2) signaling. We used human ER-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). These cells grow as tumors in nude mice and are inhibited by AIs. Despite continued treatment, tumors eventually become insensitive to AI letrozole. The cells isolated from these long-term letrozole-treated tumors (LTLT-Ca) were found to have decreased ER levels. Our results suggest that LTLT-Ca cells survive estrogen deprivation by activation of Her-2/mitogen-activated protein kinase (MAPK) pathway. Here, we show that trastuzumab (antibody against Her-2; IC₅₀ = 0.4 mg/mL) was very effective in restoring the ER levels and sensitivity of LTLT-Ca cells to endocrine therapy by down-regulation of Her-2/MAPK pathway and up-regulation of ER. In contrast, trastuzumab was ineffective in the parental hormone-responsive MCF-7Ca cells (IC₅₀ = 4.28 mg/mL) and xenografts. By blocking Her-2, trastuzumab also up-regulates ER and aromatase expression and hypersensitized MCF-7Ca cells to E₂. We show that trastuzumab is beneficial in hormone-refractory cells and xenografts by restoring ER, implicating Her-2 as a negative regulator of ER. In xenograft studies, the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone. However, on the acquisition of resistance and increased Her-2 expression, the combination of letrozole plus trastuzumab provided superior benefit over letrozole or trastuzumab alone. [Cancer Res 2009;69(4):1416–28]

This article has been cited by other articles:

				G. Sabnis, O. Goloubeva, R. Gilani, L. Macedo, and A. Brodie Sensitivity to the Aromatase Inhibitor Letrozole Is Prolonged After a "Break" in Treatment Mol. Cancer Ther., January 1, 2010; 9(1): 46 - 56. [Abstract] [Full Text] [PDF]

				S. Johnston, J. Pippen Jr, X. Pivot, M. Lichinitser, S. Sadeghi, V. Dieras, H. L. Gomez, G. Romieu, A. Manikhas, M. J. Kennedy, et al. Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer J. Clin. Oncol., November 20, 2009; 27(33): 5538 - 5546. [Abstract] [Full Text] [PDF]

				R. J. Santen, H. Brodie, E. R. Simpson, P. K. Siiteri, and A. Brodie History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target Endocr. Rev., June 1, 2009; 30(4): 343 - 375. [Abstract] [Full Text] [PDF]