Abstract
While we previously demonstrated that CITED2 expression in primary breast tumor tissues is elevated relative to normal mammary epithelium and inversely correlated with patient survival, its functional impact on primary tumor development and progression remained unknown. To address this issue, we examined the effect of CITED2 silencing on the growth of human breast cancer cell lines MDA-MB-231 and MDA-MB-468 following orthotopic administration in vivo. Here, we show that CITED2 silencing significantly attenuated MDA-MB-231 primary tumor growth concordant with reduced tumor vascularization, while MDA-MB-468 primary tumor growth and tumor vascularization remained unaffected. Correspondingly, expression of VEGFA was significantly reduced in shCITED2-expressing MDA-MB-231, but not MDA-MB-468 tumors. Consistent with the observed pattern of vascularization and VEGFA expression, we found that TGF-β stimulation induced expression of VEGFA and enhanced CITED2 recruitment to the VEGFA promoter in MDA-MA-231 cells, while failing to induce VEGFA expression in MDA-MB-468 cells. Further supporting its involvement in TGF-β-induced expression of VEGFA, CITED2 silencing prevented TGF-β induction of VEGFA expression in MDA-MB-231 cells. Collectively, these data indicate that CITED2 regulates primary breast tumor growth, likely by influencing tumor vasculature via TGF-β-dependent regulation of VEGFA.
Highlights
After lung cancer, breast cancer is the most commonly diagnosed cancer worldwide and is the second leading cause of cancer deaths in women [1]
Extending this work to breast cancer in humans, we found that CITED2 expression in primary tumor and metastatic tissues was elevated relative to normal mammary epithelium, with CITED2 levels in primary tumors inversely correlating with patient survival [7, 16,17]
Corresponding with its effects on vascularization, we demonstrate that CITED2 regulates Vascular endothelial growth factor A (VEGFA) expression, at least in part, by modulating its induction by transforming growth factor-β (TGF-β)
Summary
Breast cancer is the most commonly diagnosed cancer worldwide and is the second leading cause of cancer deaths in women [1]. While the heterogeneity of the primary tumor makes treatment challenging, it is further compounded by our limited knowledge of the key drivers of breast cancer progression. Identification of these factors and elucidation of their mechanism of action is critical to the development of novel prognostic and treatment modalities for the management of this disease. In addition to its prominent role in development, CITED2 has been implicated in malignancies such as skin, colon, and lung cancer [13,14,15]. While we demonstrated the ability of CITED2 to facilitate metastatic dissemination and colonization of secondary sites [17], its impact on early disease progression remained unknown
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