p53 in breast cancer: mutation and countermeasures

Abstract

p53 is the primary arbiter of the mammalian cell's response to stress, the governor of life and death. It is the nexus upon which signals converge from an array of sensors that detect damage to DNA or to the mitotic spindle or the cytoskeleton, hypoxia, cell detachment, growth factor deprivation, oncogene expression and other forms of stress. Depending on the type, intensity and duration of the signals, p53 in turn transactivates batteries of genes specifying cell cycle arrest, DNA repair, apoptosis, or other anti-neoplastic functions. At the same time, p53 represses anti-apoptotic and survival functions. The type, intensity and duration of signaling dictate the sequellae. While this response is combinatorial, the frequent perturbation of p53 function in a wide spectrum of cancers attests to its central role in the suppression of neoplasia. As our understanding of regulation by and of p53 has deepened, many possibilities have been suggested for re-establishing p53 or its effectors in tumor cells. This review will briefly summarize the role of p53 mutations in the etiology and treatment of breast cancer and then consider the wide array of strategies being developed to re-establish p53 function in tumor cells.

Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis

“…These results indicated that theaflavins induce apoptosis in p53-dependent manner, although in cells naturally devoid of p53 or expressing non-functional p53 a minimal p53-independent apoptosis was noticed indicating the existence of some parallel apoptotic pathways in these cells. Since at least one third of breast cancers bear mutations in p53 and to date 1400 p53 mutations have been detected in mammary epithelial carcinoma [19], it is possible that as tumors progress, the functional p53 gene is mutated and the loss of p53 function leads to the activation of alternative cell death pathways independent of p53, as was apparent in response to theaflavins. Subsequently a search for the role of transcriptional activity of p53 in theaflavin-induced apoptosis revealed that Bax, a known transcriptional target of p53 [2], was also up-regulated on theaflavin treatment.…”

The expression of PCNA, c-erbB-2, p53, ER and PR as well as atypical hyperplasia in tissues nearby the breast cancer

“…C-erB-2 is one of the common oncogene for breast cancer (McCann et al 1989;Lopez-Guerrero et al 2003); the positive expression was mainly found in poorly differentiated and invasive breast cancer. P53 is the inhibiting gene of tumorigenesis; the expression of mutant p53 could cause cell transformation and cancer (Royds and Iacopetta 2006;Kumar et al 2007;Khoury and Bourdon 2011). Last but not least, PCNA could indicate the proliferation activity of tumor cells (Kato et al 2002;Malkas et al 2006), and is important in prognosis.…”

Breast Cancer Metastasis: Advances Through the Use of In Vitro Co-Culture Model Systems

“…The model also suggests that cells being shed by the primary tumour are fully metastatic and that cells that have metastasized to a secondary site should also be able to leave that site to set up at a tertiary site (Klein 1998;Klein 2009). Mutations in genes such as BRCA1, BRCA2, p53 and RB and amplification of the HER-2 receptor at the site of the primary tumour have been identified as being predictive of poorer outcome for breast cancer patients, consistent with this model (Slamon, Clark et al 1987;Ross and Fletcher 1999;Bordeleau, Lipa et al 2007;Bosco and Knudsen 2007;Kumar, Walia et al 2007;Baker, Quinlan et al 2010). The parallel progression model suggests that tumour cells may disseminate from the site of the primary tumour very early in its development and may be subsequently genetically modified in the metastatic niche where they later settle (Klein 2009).…”