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Open Access Research

Hypoxia and estrogen are functionally equivalent in breast cancer-endothelial cell interdependence

Andrea L George, Shilpi Rajoria, Robert Suriano, Abraham Mittleman and Raj K Tiwari*

Author Affiliations

Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA

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Molecular Cancer 2012, 11:80  doi:10.1186/1476-4598-11-80

Published: 22 October 2012

Abstract

Background

Rapid breast tumor development relies on formation of new vasculature to supply the growing malignancy with oxygenated blood. Previously we found that estrogen aided in this neovasculogenesis via recruitment of bone marrow derived endothelial progenitor cells (BM-EPCs), leading to increased vessel formation and vascular endothelial growth factor (VEGF) production in vivo. However, the cellular mechanism of this induction and the signaling pathways involved need elucidation.

Results

Using the murine mammary cell line TG1-1 we observed estrogen (E2) lead to an up regulation of hypoxia inducible factor-1 (HIF-1), an effect abrogated by the anti-estrogen Fulvestrant and the HIF-1 inhibitor YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole) suggesting the interchangeability of hypoxia and estrogen mediated effects. Estrogen modulation of HIF-1 and subsequent effects on endothelial cells is dependent on the Akt/PI3K pathway and protein synthesis as validated by the use of the inhibitors wortmannin and cycloheximide which abrogated estrogen’s effects respectively. Estrogen treated TG1-1 cells secreted higher levels of VEGF which were comparable to secreted levels from cells grown under hypoxic conditions. Soluble factors in conditioned media from E2 treated breast cancer cells also lead to migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro.

Conclusions

Our data provide evidence that estrogen signaling mediates the tumor vasculogenic process required for breast cancer progression and involves a key regulator of the hypoxia signaling pathway. Further, hypoxia and estrogen are interchangeable as both similarly modulate epithelial-endothelial cell interaction.

Keywords:
Estrogen; Hypoxia; Neovasculogenesis; Vascular endothelial growth factor; Hypoxia inducible factor; Breast cancer