GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

BMC Cancer

Research Article

Binbin Yue¹  Changsheng Tian¹  Tesfom Abrhale²  Ginette Serrero³  Luciana Macedo⁴  Gauri Sabnis⁵  Angela Brodie⁵ 

[1] A&G Pharmaceutical Inc., 9130 Red Branch Rd., Columbia, MD, USA;A&G Pharmaceutical Inc., 9130 Red Branch Rd., Columbia, MD, USA;Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, 21201, Baltimore, MD, USA;A&G Pharmaceutical Inc., 9130 Red Branch Rd., Columbia, MD, USA;Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., 21201, Baltimore, MD, USA;Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, HSF-I, 685 W. Baltimore Street, 21201, Baltimore, MD, USA;Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, HSF-I, 685 W. Baltimore Street, 21201, Baltimore, MD, USA;Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., 21201, Baltimore, MD, USA;

关键词: Aromatase Inhibitor;    Letrozole;    Soft Agar;    Androstenedione;    Fulvestrant;   

DOI  :  10.1186/1471-2407-11-231

 received in 2011-03-31, accepted in 2011-06-09,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cellsMethodsWe used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.ResultsGP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.ConclusionOur findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.

【 授权许可】

Unknown   
© Abrhale et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.