Both increased Estrogen Receptor (ER)α expression and germline disruption of one

Both increased Estrogen Receptor (ER)α expression and germline disruption of one p53 allele increase breast cancer risk in women. ERα expression showed predicted higher levels of nuclear localized ERα FLT3 but this was attenuated in compound mice in association with a relative increase in Src phosphorylation. Parity protection was limited to p53 heterozygous mice and not found in mice with increased ERα alone. In summary increased and deregulated ERα collaborates with p53 heterozygosity in increasing the risk of mammary preneoplasia development. (DCIS) and invasive breast cancer (2). Breast cancer is associated with somatic genetic and epigenetic alterations in the breast tissue such as tumor suppressor gene mutation or other molecular changes that compromise their function. The tumor suppressor p53 plays a role in mediating cell response to various stresses by inducing or repressing genes involved in cell cycle arrest senescence apoptosis DNA repair and angiogenesis (3). Alterations to p53 are commonly detected in primary human breast tumors (4) reported in 30-40% of human breast cancers (5) and about 25% of all preinvasive DCIS lesions(6). Disruption of p53 function may be involved in earlier rather than later stages of breast cancer progression such as initiation of breast carcinogenesis and impaired differentiation of DCIS (7 8 Alterations to p53 function include mutation changes in upstream regulators transcriptional target genes and coactivators (9). p53 detection in benign lesions indicative of possible mutation is associated with elevated cancer risk (10). In DCIS p53 is associated with more advanced lesions (11) and is a predictor for local recurrence (12 13 In cancers loss or mutation of p53 is correlated with increased aggressiveness poor prognosis (14) and chemotherapy resistance (15). In addition to p53 somatic mutation in sporadic cancers germline mutation of one allele of this gene in humans causes an inborn predisposition to cancer known as Li-Fraumeni syndrome (16) where early-onset female breast cancer is the most prevalent tumor type (17). Hormone receptor status is one of the main differentiating characteristics of human breast cancers and modifies therapeutic response. About 60-70% of human breast cancers are estrogen receptor α (ERα) positive and estrogen-dependent (18). Increased ERα expression in normal breast epithelium is found in conjunction with breast cancer leading to the concept that MK-8033 loss MK-8033 of the normal regulatory mechanisms that control expression levels of ERα in normal breast epithelium may increase the risk for the development of breast cancer (19). Increased and deregulated ERα expression in the mammary epithelial cells of transgenic mice (CERM) results in the development of ductal carcinoma and increased cell proliferation (20). Expression of ERα is increased two-fold in the mammary epithelial cells of these mice and is considered deregulated because it is not down-regulated MK-8033 by estrogen exposure. Reproductive history is the strongest and most consistent risk factor outside of genetic background and age (21). Early pregnancy in reproductive life reduces breast cancer lifetime risk in women by up to 50% (22 23 In mouse models MK-8033 p53 is required for hormonal protection from mammary tumorigenesis (24). Early exposure to estrogen and progesterone designed to mimic pregnancy has been found to enhance p53-dependent responses increase resistance to carcinogenesis by blocking proliferation of ERα-positive cells (25) and suppress mammary tumor formation in BALB/c-Trp53+/? mice (26). Different observations point to potential cross-talk between p53 and ERα. Human breast cancers with p53 mutations are more frequently ER-negative (27). In serial transplant studies absence of p53 in mammary epithelium is associated with DCIS lesions and invasive cancer that progress from an ERα-positive to ERα-negative state (28 29 Studies have shown that p53 can regulate ERα expression and transcriptional activity but both positive and negative effects have been shown (30 31 ERα can also be regulated at the protein level. c-Src phosphorylation has been shown to stimulate ERα ubiquitylation and proteasome-dependent degradation (32) and p53 has been reported to down-regulate some Src functions (33). The effects of MK-8033 loss of p53 and ERα deregulation on cell proliferation and apoptosis during carcinogenesis have been previously.

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