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

Tesfom Abrhale,Ginette Serrero,Changsheng Tian,Luciana Macedo,Binbin Yue,Angela Brodie,Gauri Sabnis

doi:10.1186/1471-2407-11-231

Tesfom Abrhale, Ginette Serrero + Show 5 more

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https://doi.org/10.1186/1471-2407-11-231

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Abstract

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.

Highlights

Aromatase 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
This phenomenon was demonstrated for the overexpression of multiple growth factors and their receptors, including heregulins acting through HER3 and HER4 [13,14], epidermal growth factor [15] and transforming growth factor (TGF)-a acting through the epidermal growth factor receptor (EGFR) [16,17], insulin-like growth factors IGF-I and IGF-II acting through the IGF-IR [18,19], and HER2 receptor contributing to anti-hormone failure either directly when overexpressed [20,21,22,23] or indirectly through heterodimerization with other erbB receptor family members [17]
GP88 induces cell proliferation and confers letrozole resistance in vitro We examined the effect of human GP88 on proliferation and letrozole responsiveness of MCF-7 AC1 human breast cancer cells overexpressing aromatase

Summary

Introduction

Aromatase 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. Treatment options for patients with hormone-dependent ER+ breast cancers are estrogen antagonist such as tamoxifen, estrogen receptor down regulator such as Fulvestrant or inhibitors of estrogen biosynthesis such as aromatase inhibitors [6,7]. It is widely documented that the inappropriate activation of growth factor signaling cascades, either through overexpression of growth factor, or via up-regulation and increased activation of their target growth factor receptors or their recruited downstream signaling elements, can readily promote anti-hormone failure in breast cancer cells [10,11,12]. This phenomenon was demonstrated for the overexpression of multiple growth factors and their receptors, including heregulins acting through HER3 and HER4 [13,14], epidermal growth factor [15] and transforming growth factor (TGF)-a acting through the epidermal growth factor receptor (EGFR) [16,17], insulin-like growth factors IGF-I and IGF-II acting through the IGF-IR [18,19], and HER2 receptor contributing to anti-hormone failure either directly when overexpressed [20,21,22,23] or indirectly through heterodimerization with other erbB receptor family members [17]

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