The p53 pathway in breast cancer

Abstract

ASPP = apoptosis stimulating protein of p53; A-T = ataxia-telangectasia; ATM = ataxia-telangectasia mutated; ATR = ataxia-telangectasia and Rad3-related protein; Chk2 = human homologue of Rad53; DCIS = ductal carcinoma in situ; LOH = loss of heterozygosity; maspin = mammary serine protease inhibitor; MDM2 = mouse double minute 2; p14 ARF = alternative product of the INK4 gene; σ = 14-3-3sigma.Available online http://breast-cancer-research.com/content/4/2/070 IntroductionFirst described in 1979, and initially believed to be an oncogene, p53 was the first tumour suppressor gene to be identified. p53 functions to eliminate and inhibit the proliferation of abnormal cells, thereby preventing neoplastic development. Abrogation of the negative growth regulatory functions of p53 occurs in many, perhaps all, human tumours. The p53 signalling pathway is in 'standby' mode under normal cellular conditions. Activation occurs in response to cellular stresses, and several independent pathways of p53 activation have been identified that appear to be dependent on distinct upstream regulatory kinases [1] (Fig. 1). These include an ataxia-telangectasia mutated (ATM)/human homologue of Rad53 (Chk2)-dependent pathway activated by DNA double-strand breaks, a second pathway dependent on the alternative product of the INK4 gene, p14 ARF (which is activated by expression of oncogenes), and a third pathway whose activity is increased by cytotoxic anti-tumour agents and ultraviolet light, but is independent of ATM, Chk2 and p14 ARF . Activation of this pathway may be mediated by other kinases such as the ATM relative ataxiatelangectasia and Rad3-related protein (ATR) [1].Activation results in an increase in the levels of p53 protein due to reduced mouse double minute 2 (MDM2)-dependent proteolytic degradation, and increased affinity of p53 for DNA. Whereas phosphorylation of the N-terminus may affect the stability of p53, lysine acetylation and/or serine phosphorylation in the C-terminus of the protein promotes DNA binding. As a result of activation, the wild-type protein acquires sequence-specific DNA binding activity, and an increasing number of genes are being identified as transcriptional targets of wild-type p53 [2]. These can be placed into a number of classes according to their functions. Abstract p53 mutation remains the most common genetic change identified in human neoplasia. In breast cancer, p53 mutation is associated with more aggressive disease and worse overall survival. The frequency of mutation in p53 is, however, lower in breast cancer than in other solid tumours. Changes, both genetic and epigenetic, have been identified in regulators of p53 activity and in some downstream transcriptional targets of p53 in breast cancers that express wild-type p53. Molecular pathological analysis of the structure and expression of constituents of the p53 pathway is likely to have value in diagnosis, in prognostic assessment and, ultimately, in treatment of breast cancer. Review The p53 pathway in breast cancer

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…P53 is mutated in approximately 50% of human breast cancers, and the pathway is probably disabled in even higher percentages of cases (Gasco et al, 2002). Loss of p53 does not inhibit the expression of ER in normal mammary cells, since ER is expressed in p53-null mammary epithelia (data not shown and Medina et al, 2003).…”

Expression Analysis of MiR-21, MiR-205, and MiR-342 in Breast Cancer in Iran

“…P53, which encodes a tumor suppressor protein, has various effects on cell cycle arrest and apoptosis, and it also increases the expression of the proteins involved in DNA repair (Gasco et al, 2002). Mutations in receptor coding genes, HER2 (Human Epidermal growth factor Receptor 2), ER (Estrogen Receptor) and PR (Progesterone Receptor) are very important because they may change the treatment strategy of cancer.…”

“…P53 is the most common gene which is mutated in malignant cancers (Gasco et al, 2002). P53, which encodes a tumor suppressor protein, has various effects on cell cycle arrest and apoptosis, and it also increases the expression of the proteins involved in DNA repair (Gasco et al, 2002).…”

Detection of mutations within exons 4 to 8 of the p53 tumor suppressor gene in canine mammary glands

“…Zootec., v.64, n.2, p. [341][342][343][344][345][346][347][348]2012 localized between exons 5 to 8 (Van Leeuwen et al, 1996;Walker e Rapley, 1999;Muto et al, 2000;Setoguchi et al, 2001;Philibert et al, 2003;Moura-Gallo et al, 2004). In human breast cancer, Tp53 mutation is associated to more aggressive diseases and a worse prognosis for patient survival (Gasco et al, 2002).…”