Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin. [Cancer Res 2007;67(13):6183-91]
Our laboratory has delineated that the phosphatidylinositol 3 0 kinase (PI3K)/AKT/IjB kinase (IKK) pathway positively regulates NFjB and b-catenin, both important transcriptional regulators in colorectal cancer (CRC). Therefore, we investigated the effect of inhibiting the PI3K/AKT/IKKa pathway in regulating the inappropriate constitutive activation of NFjB and b-catenin in CRC cell lines. SW480 and RKO CRC cell lines demonstrate constitutive activation of AKT as well as both NFjB-and b-catenin-dependent transcription. The constitutive activation of NFjB-and b-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKKa, which blocks IKKa kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity. The ability of KD IKKa, KD AKT or WT PTEN to decrease b-catenindependent transcription is independent of their effects on NFjB. Inducible expression of either KD IKKa or WT PTEN strongly inhibits both the constitutive NFjB-and b-catenin-dependent promoter and endogenous gene activation. Targeted array-based gene expression analysis of this inducible system reveals that many of the genes downregulated upon inhibition of this pathway are involved in tumor angiogenesis and metastasis. The activation of this pathway and the expression of the three most repressed genes was further analysed in samples of CRC. These results indicate a role of this pathway in controlling gene expression important in tumor progression and metastasis.
Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-KB (NF-KB). To further investigate the role of NF-KB in BRMS1-regulated gene expression, we examined NF-KB binding activity and found an inverse correlation between BRMS1 expression and NF-KB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-A-induced NF-KB activation by BRMS1 may be due to inhibition of IKBA phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P < < < < < 0.0001) and a general inverse correlation with uPA gene expression (P < < < < < 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-KB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells. (Cancer Res 2005; 65(9): 3586-95)
Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1protein expression correlated with genomic copy number changes. Experimental Design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1staining. Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P = 0.006) or HER2 positive (P = 0.039) and <50 years old at diagnosis (P = 0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1protein expression and reduced disease-free survival when stratified by either loss of ER (P = 0.008) or PR (P = 0.029) or HER2 overexpression (P = 0.026). Overall, there was poor correlation between BRMS1protein staining and copy number status. Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.The breast cancer metastasis suppressor 1 (BRMS1) is one of a growing number of genes that have the ability to suppress metastasis without affecting tumorigenicity in experimental in vivo models (1 -4). BRMS1 maps to chromosome 11q13, a region where nonrandom amplification and deletions have been associated with progression and metastasis in breast cancer patients (5). BRMS1 is a predominantly nuclear protein that contains an imperfect leucine zipper motif and coiledcoiled domains, implying that it may function as part of a transcriptional complex (1), and recent studies suggest that BRMS1 may inhibit metastasis, in part, through gene regulation via interaction with histone deacetylases (6, 7). The restoration of BRMS1 expression was recently shown to correlate with reduced phosphoinositide and nuclear factor nB signaling, suggesting specific mechanisms by which BRMS1 may regulate genes involved in the metastatic process (8,9).Despite the potential importance of BRMS1 as a determinant of metastasis in the clinical setting, the study of patient samples from human breast cancer has been hampered by the lack of antibodies to native BRMS1 (6). The recent development of suitable antibodies to BRMS1 now makes it possible to study primar...
Background: Osteopontin (OPN), a secreted phosphoglycoprotein, has been strongly associated with tumor progression and aggressive cancers. MDA-MB-435 cells secrete very high levels of OPN. However metastasis-suppressed MDA-MB-435 cells, which were transfected with breast cancer metastasis suppressor 1 (BRMS1), expressed significantly less OPN. BRMS1 is a member of mSin3-HDAC transcription co-repressor complex and has been shown to suppress the metastasis of breast cancer and melanoma cells in animal models. Hence we hypothesized that BRMS1 regulates OPN expression.
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