ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells

Abstract

BackgroundZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response.ResultsWe provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation in vitro associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells.ConclusionAltogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects.

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

“…These cell lines have been described to show resistance to PTX (37)(38)(39). We confirmed that PTX had almost no effect on TS/ApGL3 cell viability and reduced MDA-MB-231 and MDA-MB-231-ZNF217rvLuc2 cell viability by only 30% to 40% over 24 to 48 hours, relative to vehicle control ( Supplementary Fig.…”

An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

“…Furthermore, ZNF217 has a demonstrated role in promoting proliferation in several models of breast cancer. Specifically, silencing of ZNF217 results in reduced proliferation in several breast cancer cell lines (including MCF-7), and overexpression of ZNF217 increases proliferation in the same cell lines as well as in xenograft tumors (Thollet et al 2010). The established role of ZNF217 as an oncogene combined with these findings strongly support miR-503 as a candidate tumor suppressor in breast cancer.…”

“…In this study, we identify three major patterns of gene expression following estrogen stimulation: (i) transient, (ii) induced, and (iii) repressed. Among the genes repressed by estrogen stimulation is the oncogene ZNF217, which has been shown to enhance proliferation in ovarian ) and breast cancer (Thollet et al 2010). Additionally, we have shown that the estrogen-induced miRNA, miR-503, targets the 3 ′ -UTR of ZNF217 and that while miR-503 is induced in response to estrogen, the oncogene ZNF217 is reduced.…”

ZNF217 Is a Marker of Poor Prognosis in Breast Cancer That Drives Epithelial–Mesenchymal Transition and Invasion

“…MDA-MB-231-pcDNA6, ZNF217-1, and ZNF217-2 cells have been described previously (11). Populations of MCF10A-pcDNA6 and MCF10A-ZNF217 stable transfectants were obtained using the same plasmid and selection process as described in Thollet and colleagues (11).…”

“…Previous studies have found that high levels of ZNF217 expression have been associated with resistance to chemotherapy and with deregulated apoptotic signals in breast cancer cells (10,11). The precise molecular mechanisms involved in ZNF217 prosurvival functions are currently unknown, but activation of the Akt pathway (10), ErbB3 overexpression (12), Aurora-A overexpression (11), deregulated expression of several members of the Bcl-2 family (11), eEF1A2 overexpression (13), and interaction with the HIF pathway (14) have been proposed.…”