GP88 PC-Cell Derived Growth Factor, progranulin stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cellsReportar como inadecuado

GP88 PC-Cell Derived Growth Factor, progranulin stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Cancer

, 11:231

Experimental therapeutics and drug development


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 cells

MethodsWe 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.

List of AbbreviationsADandrostenedione

AIaromatase inhibitors

E217-β estradiol

ERestrogen receptor

FBSfetal bovine serum

ChX-FBScharcoal extracted fetal bovine serum


PRF mediumphenol red free medium

PRF-ChXphenol red free DME-F12 medium supplemented with 5% Charcoal extracted fetal bovine serum

SDSsodium dodecyl sulfate

PAGEpolyacrylamide gel electrophoresis

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-11-231 contains supplementary material, which is available to authorized users.

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Autor: Tesfom Abrhale - Angela Brodie - Gauri Sabnis - Luciana Macedo - Changsheng Tian - Binbin Yue - Ginette Serrero


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