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|Abstract:||The TP53 gene, which encodes the p53 protein, is the most frequent target for mutation in tumors, with over half of all human cancers exhibiting mutation at this locus (Vogelstein et al., 2000). Wild-type p53 functions primarily as a transcription factor and possesses an Nterminal transactivation domain, a centrally located sequence specific DNA binding domain, followed by a tetramerization domain and a C-terminal regulatory domain (Laptenko and Prives, 2006). Unlike most tumor suppressor genes, which are predominantly inactivated as a result of deletion or truncation, the majority of mutations in TP53 are missense mutations, a few of which cluster at “hotspot” residues in the DNA binding core domain (Petitjean et al., 2007). In contrast to wild-type p53, which under unstressed conditions is a very short-lived protein, these missense mutations lead to the accumulation of full-length p53 protein with a prolonged half-life (Brosh and Rotter, 2009). While many tumor-derived mutant forms of p53 can exert a dominant-negative effect on the remaining wild-type allele, the end result in many forms of human cancer is frequently loss of heterozygosity, where only the mutant form is retained, suggesting that there is a selective advantage conferred by losing the remaining wild-type p53, even after one allele has been mutated (Brosh and Rotter, 2009). Mutant forms of p53 can exert oncogenic, or gain-of-function, activities independent of their effects on wild-type p53. In vivo knock-in mice harboring two tumor-derived mutants of p53 (equivalent to R175H and R273H in humans) display an altered tumor spectrum as well as more metastatic tumors when compared to p53 null mice (Lang et al., 2004; Olive et al., 2004). The mutational status of p53 has been shown to predict poor outcomes in multiple types of human tumors, including breast cancer, and certain p53 mutants associate with an even worse prognosis (Olivier et al., 2006; Petitjean et al., 2007). Mutant p53 expression correlates with increased survival, invasion, migration and metastasis in preclinical breast cancer models (Adorno et al., 2009; Muller et al., 2009; Stambolsky et al., 2010). Nonetheless, mutant p53-induced phenotypic alterations in mammary tissue architecture have not been fully explored. Breast cancer is thought to arise from mammary epithelial cells found in structures referred to as acini, which collectively form terminal ductal lobular units. Each acinus consists of a single layer of polarized luminal epithelial cells surrounding a hollow lumen (Bissell et al., 2002). While traditional two-dimensional (2D) cell culture has provided insight into the process of breast carcinogenesis, such in vitro culture conditions differ from the microenvironment that a cell would experience in vivo (Bissell et al., 2002). By contrast, a laminin-rich extracellular matrix allows normal mammary epithelial cells to form threedimensional structures reminiscent of acinar structures found in vivo (Petersen et al., 1992). Since one of the hallmarks of breast tumorigenesis is the disruption of mammary tissue architecture, three-dimensional (3D) culture conditions allow one to readily distinguish normal and tumorigenic tissue by morphological phenotype (Petersen et al., 1992). In addition, inhibition of key oncogenic signaling pathways is sufficient to phenotypically revert breast cancer cells grown in 3D culture (Bissell et al., 2005). Here we implicate mutant p53 and the mevalonate pathway in the disruption of acinar morphology and our data have also revealed a potential mechanism by which mutant p53 increases expression of the genes in the mevalonate pathway.|
|Citation:||Freed-Pastor, William A, Mizuno, Hideaki, Zhao, Xi, Langerød, Anita, Moon, Sung-Hwan, Rodriguez-Barrueco, Ruth, Barsotti, Anthony, Chicas, Agustin, Li, Wencheng, Polotskaia, Alla, Bissell, Mina J, Osborne, Timothy F, Tian, Bin, Lowe, Scott W, Silva, Jose M, Børresen-Dale, Anne-Lise, Levine, Arnold J, Bargonetti, Jill, Prives, Carol. (2012). Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway. Cell, 148 (1-2), 244 - 258. doi:10.1016/j.cell.2011.12.017|
|Pages:||244 - 258|
|Type of Material:||Journal Article|
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