Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2

Abstract

CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

CCN5/WISP-2 Expression in Breast Adenocarcinoma Is Associated with Less Frequent Progression of the Disease and Suppresses the Invasive Phenotypes of Tumor Cells

“…However, their effect in terms of offering new concepts of the molecular network of human breast cancer development, diagnostics, or therapeutic modalities remains limited. Over the last several years, after the identification of CCN5 in noninvasive human breast tumor cells and samples by using RNA differential display analysis (14), CCN5 has been implicated as having an important role in human breast disease and other cancers as well (9,10,14,20,(29)(30)(31)(32)(33). The present immunohistochemical and in situ hybridization analysis studies have shown a differential expression profile of CCN5 in human breast samples.…”

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

“…[19][20][21] Briefly, 50 μg total protein was separated by SDS-PAGE and transferred to nitrocellulose membrane (Trans-blot transfer medium, Bio-Rad). The membranes were probed with primary antibodies for a specified period of time as per the manufacturer's instructions.…”

CCN5/WISP-2: A micromanager of breast cancer progression

“…For example, silencing of CCN5 in MCF-7 non-invasive carcinoma cells by CCN5-specific shRNA significantly enhances motility and EMT, and it modulates the expression of some genes associated with invasive phenotypes of cancer cells Dhar et al 2008;Fritah et al 2008). In CCN5 knockout ER-α positive breast cancer cells, IGF-1 and EGF lost their mitogenic effect Dhar et al 2007b), but possibly gained aggressive phenotypes (i.e., Fig.…”