Wild-type p53 controls the level of fibronectin expression in breast cancer cells

Abstract

Abstract. Aberrant fibronectin (FN) expression is associated with poor prognosis, cell adhesion, and cell motility in a variety of cancer cells. In this study, we investigated the relationship between p53 and FN expression in breast cancer cells. Basal FN expression was significantly decreased by treatment with the p53 activator III, RITA, in MCF7 breast cancer cells with wild-type p53. In addition, overexpression of wild-type p53 markedly decreased the level of FN expression in p53-mutant breast cancer cells. To examine the mechanism underlying the relationship between p53 and FN expression, we treated MCF7 breast cancer cells with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate). Our results showed that basal FN expression was increased by TPA treatment in a time-dependent manner. In contrast, the level of p53 expression was decreased by TPA treatment. However, the expression of FN and p53 was not altered by TPA in p53-mutant breast cancer cells. Furthermore, the alterations in FN and p53 expression in response to TPA were prevented by a specific MEK inhibitor, UO126. Finally, we demonstrated that TPA triggers degradation of p53 through the proteasomal pathway in MCF7 cells. TPA-induced FN expression was decreased by the proteasome inhibitor MG132. Under the same condition, p53 protein expression, but not mRNA expression, was reversed by MG132. Taken together, our data demonstrate that the level of FN expression is associated with the status and expression of p53 in breast cancer cells. IntroductionFibronectin (FN) is one of the most abundant adhesive glycoproteins of the extracellular matrix and acts as a substrate for cell adhesion during wound healing and metastasis (1). The complex of integrin and FN can have modulating effects on various signaling pathways including focal adhesion kinase (FAK), signal transducer and activator of transcription-3 (STAT-3), and mitogen-activated protein kinase (MAPK) pathways that promote cell invasion and metastasis in multiple cancer cells (2-4). The induction of FN by HER2 overexpression triggers cell adhesion and invasion capacities in breast cancer cells (5). In addition, excessive FN expression is linked to poor metastatic-free survival and overall survival in breast cancer patients (6,7).The tumor suppressor protein p53 is a transcription factor that can trigger cell cycle arrest, replicative senescence, or apoptosis (8). The induction of p53 expression by a wide variety of cellular stresses such as hypoxia, UV, and cytotoxic drugs is involved in accelerated cellular senescence as well as G1/S and G2/M cell cycle checkpoint activation (9-11). The TP53 gene encoding p53 is the most frequently inactivated gene in human malignancy, and somatic missense mutations of p53 are found in ~50% of human cancers (12). Mutations in the TP53 gene result in loss of wild-type p53 tumor suppressor functions (13). Wild-type p53 upregulates p21, the negative regulator of cyclin-dependent kinases (cdks), whereas mutant p53 enhances cdk1 and increases cell proliferation and s...

Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

“…An important finding in this study was that FN1 mRNA and protein expression were significantly increased in p53-KD cells, while FN1 promoter activity was repressed by p53wt, but not p53mt, in line with other studies [47,48]. Moreover, treatment of OCCCa cells with FN resulted in an enhanced migration capability and a reduced proliferation rate.…”

Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

“…An important finding in this study was that FN1 mRNA and protein expression were significantly increased in p53-KD cells, while FN1 promoter activity was repressed by p53wt, but not p53mt, in line with other studies [48,49]. Moreover, treatment of OCCCa cells with FN resulted in an enhanced migration capability and a reduced proliferation rate.…”

Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

“…An important finding in this study was that FN1 mRNA and protein expression were significantly increased in p53-KD cells, while FN1 promoter activity was repressed by p53wt, but not p53mt, in line with other studies [38,39]. Moreover, treatment of OCCCa cells with FN resulted in an enhanced migration capability and a reduced proliferation rate.…”