Abstract
Overexpression of Notch1 has been associated with breast cancer. We recently showed that visfatin stimulates breast cancer cell proliferation and invasion. The present study was undertaken to determine whether Notch1 signaling is affected by visfatin and to characterize the functional role of the visfatin-Notch1 axis in breast cancer. Visfatin and Notch1 were expressed at higher levels in breast tumors than in matched control tissues. Visfatin induced Notch1 expression in MDA-MB-231 breast cancer cell line and in nontransformed MCF10A mammary epithelial cells, whereas visfatin depletion reduced Notch1 mRNA and protein levels. Depletion of Notch1 in MDA-MB-231 cells attenuated cell growth in vitro and in vivo; visfatin depletion produced similar effects, but was less potent. Additionally, Notch1 depletion inhibited cell proliferation induced by visfatin. Analysis of the signaling pathways underlying visfatin-mediated Notch1 upregulation revealed that visfatin activated NF-κB p65. Blockade of NF-κB signaling suppressed the effects of visfatin on Notch1 upregulation and breast cancer cell proliferation. Breast tumors expressing high levels of NF-κB p65 exhibited increased expression of Notch1. Our results demonstrate that the visfatin-Notch1 axis contributes to breast tumor growth through the activation of the NF-κB pathway. Study of the visfatin-Notch1 axis may offer new therapeutic directions for breast cancer.
Highlights
Breast cancer is the most common cancers among women worldwide [1]
To examine the role of visfatin in the regulation of Notch1 in breast cancer cells, MDA-MB-231 human breast cancer cells were treated with visfatin for the indicated times and www.impactjournals.com/oncotarget measured the levels of Notch1 mRNA and protein by quantitative real-time RT-PCR (qRT-PCR)/Reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively
Because NF-κB p65 mediated visfatin-induced Notch1 upregulation, we investigated whether a correlation between NF-κB p65 and Notch1 expression existed in human breast cancer tissues
Summary
Recent studies indicate that obesity is a significant risk factor for breast cancer [2]. The influences of obesity and increased adiposity on the risk of breast cancer are partially explained by the changes in adipokines secreted from adipose tissue and from the epithelial tissue of breast tumors [3]. Several adipokines, including leptin [3,4,5], resistin [3, 6], and hepatocyte growth factor [3, 7], have been associated with an increased risk of breast cancer. The adipokine visfatin, known as pre-B-cell colony-enhancing factor [8], is predominantly secreted [8], but it localizes to the nucleus and cytosol [9]. Visfatin is highly expressed in human breast cancer cells both in vitro and in vivo [17,18,19], and it increases the proliferation and DNA synthesis rate of human breast www.impactjournals.com/oncotarget cancer cells [20], suggesting that visfatin may contribute to breast cancer growth
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