Abstract
Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ‘normal’ estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that Cyr61 is sufficient to induce MCF-7 cells to grow in the absence of E2. Cyr61-transfected MCF-7 cells (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7 cells transfected with the vector DNA (MCF-7/V) remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERα expression in MCF-7/Cyr61 cells is decreased although still functional. Moreover, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and antiestrogen-resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.
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Acknowledgements
The authors thank Drs Judith Campisi and Nechama Smorodinsky for scientific discussion and Kevin Peet for editorial assistance. The authors would also like to thank Eddie Lo, Inderjit Mehmi, and Dr Ella Atlas for technical support during the course of this work. This work was supported by a grant from the National Institutes of Health (Contract No. DK49049), and the Department of Energy under Contract No. DE-AC03-76SF00098 (R Lupu), and the Breast Cancer Research Program Postdoctoral Traineeship from the Department of Defense (M-S Tsai).
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Tsai, MS., Bogart, D., Castañeda, J. et al. Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 21, 8178–8185 (2002). https://doi.org/10.1038/sj.onc.1205682
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DOI: https://doi.org/10.1038/sj.onc.1205682
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