Protein 4.1B suppresses prostate cancer progression and metastasis

Howard Hughes Medical Institute, Massachusetts Institute of Technology Center for Cancer Research, Cambridge, MA 02139, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2007; 104(31):12784-9. DOI: 10.1073/pnas.0705499104
Source: PubMed


Protein 4.1B is a 4.1/ezrin/radixin/moesin domain-containing protein whose expression is frequently lost in a variety of human tumors, including meningiomas, non-small-cell lung cancers, and breast carcinomas. However, its potential tumor-suppressive function under in vivo conditions remains to be validated. In a screen for genes involved with prostate cancer metastasis, we found that 4.1B expression is reduced in highly metastatic tumors. Down-regulation of 4.1B increased the metastatic propensity of poorly metastatic cells in an orthotopic model of prostate cancer. Furthermore, 4.1B-deficient mice displayed increased susceptibility for developing aggressive, spontaneous prostate carcinomas. In both cases, enhanced tumor malignancy was associated with reduced apoptosis. Because expression of Protein 4.1B is frequently down-regulated in human clinical prostate cancer, as well as in a spectrum of other tumor types, these results suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease.

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    • "Different expression patterns and activities of SPARC are depending on cancer type and upon whether it is expressed by malignant cells themselves or by neighboring stromal cells [Tai and Tang, 2008]. SPARC expression is associated with a favorable prognosis in some studies on human prostate cancer [Welsh et al., 2001; Lapointe et al., 2004; Wong et al., 2007]. In these studies SPARC may indeed function as a tumor suppressor since down‐regulation and inactivation of SPARC gene expression enhanced aggressive and metastatic behavior. "
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    • "Loss of expression or function of tumor metastasis suppressors is requisite for the development of local invasion and distant metastases (Smith and Theodorescu 2009). Previous studies have described several potential metastasis suppressor genes in PCa (Thiolloy and Rinker-Schaeffer 2010, Wong et al 2007). EPLIN was initially identified as an epithelial protein that is abundantly expressed in normal epithelia but significantly downregulated at mRNA level in a limited number of cancerous cells (Maul and Chang 1999). "
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    • "Conversely, loss of Protein 4.1B, another member of the same superfamily [3], has been shown to lead to an enhanced metastatic capacity during the induction of human adenocarcinoma PC-3 cells into immunodeficient mice [10]. These studies support the conclusion that not all members of this superfamily have the same effects on carcinogenic processes. "
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