Cyclin D1, Id1 and EMT in breast cancer

Abstract

BackgroundCyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1 and EMT, as well as clinical properties in primary breast cancer.MethodsProtein and gene expression of ID1, CCND1 and EMT markers were determined in MDA-MB-231 and ZR75 cells by western blot and qPCR. Cell migration and promoter occupancy were monitored by transwell and ChIP assays, respectively. Gene expression was analysed from publicly available datasets.ResultsThe increase in cell migration following cyclin D1 silencing in MDA-MB-231 cells was abolished by Id1 siRNA treatment and we observed cyclin D1 occupancy of the Id1 promoter region. Moreover, ID1 and SNAI2 gene expression was increased following cyclin D1 knock-down, an effect reversed with Id1 siRNA treatment. Similar migratory and SNAI2 increases were noted for the ER-positive ZR75-1 cell line, but in an Id1-independent manner. In a meta-analysis of 1107 breast cancer samples, CCND1low/ID1high tumours displayed increased expression of EMT markers and were associated with reduced recurrence free survival. Finally, a greater percentage of CCND1low/ID1high tumours were found in the EMT-like 'claudin-low' subtype of breast cancer than in other subtypes.ConclusionsThese results indicate that increased migration of MDA-MB-231 cells following cyclin D1 silencing can be mediated by Id1 and is linked to an increase in EMT markers. Moreover, we have confirmed a relationship between cyclin D1, Id1 and EMT in primary breast cancer, supporting our in vitro findings that low cyclin D1 expression can be linked to aggressive features in subgroups of breast cancer.

The Breast Cancer Susceptibility Gene Product Fibroblast Growth Factor Receptor 2 Serves as a Scaffold for Regulation of NF-κB Signaling

“…Stimulation by its ligands leads to the dissociation of IB from NF-B and degradation through the ubiquitin/ proteasome-dependent pathway (17,18). The released NF-B translocates into the nucleus and activates downstream genes, including matrix metalloproteinase-9 to promote cell invasiveness (19), TRAF1 and -2 to evade apoptosis (2), cyclin D1 to facilitate cell proliferation (29), and the oncoprotein c-Myc, which is also linked to poor cancer outcome (33). Moreover, IB kinases (IKKs) regulate Myc protein stability, further enhancing breast cancer progression (31).…”

Inhibitor of DNA-binding protein 1 knockdown arrests the growth of colorectal cancer cells and suppresses hepatic metastasis in vivo

“…For example, ID1 was found to elevate the expression of epithelial mesenchymal markers in nicotine and EGF-induced proliferation, migration and invasion of nonsmall cell lung cancer (23). Similarly, ID1 was found to be positively associated with the migratory and invasive features of breast cancer cells by enhancing epithelial-mesenchymallike markers (28). A clinical observation indicated that ID1 expression was strongly associated with lymph node metastasis in patients with CRC (13).…”

Growth and gene expression differ over time in alpha-linolenic acid treated breast cancer cells

“…Changes in gene expression from ALA treatment independent of time were also observed in MDA-MB-231 cells, including a reduction in ID1, and increases in JUN, NME1, and THBS1. The inhibitor of DNA binding protein, ID1, has been linked in MDA-MB-231 cells to cyclin D1 silencing and increased cell migration and invasiveness [43], and angiogenesis [30]. Thus the ability of ALA to reduce the expression of ID1 in MDA-MB-231 cells may lead to decreases in cell growth.…”