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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

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

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Andrea L George, Shilpi Rajoria, Robert Suriano, Abraham Mittleman, Raj K Tiwari
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-80) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

ALG contributed to conception and design of the study, carried out western blot, immunoflourescent, migration, and tubulogenesis studies, and contributed to drafting of the manuscript. SR participated in acquisition of data and drafting of the manuscript, RS participated in analysis and interpretation of the data and revising of the manuscript/contributing to intellectual content, AM provided reagents/analysis tools and contributed to intellectual content of the manuscript, RKT helped conceive the study, participated in design and coordination of the study and drafting the manuscript. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
12943_2011_1044_MOESM1_ESM.pdf
Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Literatur
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