Breast cancer in postmenopausal women: what is the real risk?

Cutler, Winnifred B.; Bürki, Regula E.; Genovesse, E.; Zacher, Millicent

doi:10.1016/j.fertnstert.2009.07.061

Cited by 2 publications

(2 citation statements)

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“…Association of the p53 mutation was found significant with gender postmenopausal status, histological grade and ALN involvement which was consistent with existing data in the literature (Giordano et al, 2004;Cutler et al, 2009;Madigan et al, 1995). Our sequencing data revealed p53 gene mutations in 29 (47%) tumor biopsies from different individuals.…”

Section: Discussionsupporting

confidence: 91%

P53 Gene: Mutation and Immunohistochemical Analysis in Patients With Invasive Ductal Carcinoma of Breast

Singh

Rajput

Singh

et al. 2013

American Journal of Biochemistry and Biotechnology

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The p53 tumor suppressor gene is the most commonly mutated gene in cancer. In breast cancer, the presence of p53 gene alterations has been associated with worse prognosis. This study was attempted to associate p53 gene mutations with its protein expression in North Eastern Indian population. We used single-stranded conformation polymorphism to screen samples for mutations in five conserved regions, exons 4, 5, 6, 7 and 8, of the p53 gene. Mutations were confirmed by direct DNA sequencing. Samples were also analyzed for expression of p53 immunohistochemically. We found two critical mutations in the exon 4. A well known missense mutation at codon 72 (pro to arg) with a frequency of 47% was found which was significantly correlated with the immunohistochemical analysis of p53 protein in such patients. A novel nonsense mutation at codon 107 which leads to stop codon was also found. Although the occurrence of this mutation was very less, we did not find expression of p53 protein immunohistochemicaly. We support that mutation in p53 gene can be exploited as a prognostic marker for the early diagnosis of breast cancer, although more clinical and epidemiological data is required to establish this claim.

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Section: Discussionsupporting

confidence: 91%

P53 Gene: Mutation and Immunohistochemical Analysis in Patients With Invasive Ductal Carcinoma of Breast

Singh

Rajput

Singh

et al. 2013

American Journal of Biochemistry and Biotechnology

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“…Breast cancer is a leading cause of cancer among women in the United States and approximately 60% to 70% of these breast cancers express estrogen receptor alpha (ERα) [ 1 - 3 ]. Estrogen binding to ERα induces both genomic and nongenomic actions of the ER, which ultimately lead to increased breast cancer cell growth.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim

et al. 2012

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Introduction In this pre-clinical in vitro study conducted in estrogen receptor positive (ER+) breast cancer cells, we have characterized the effects of insulin-like growth factor I (IGF-1) on the cytostatic and cytotoxic action of antiestrogen treatment when used as a single agent or in combination with the antiprogestin mifepristone (MIF). Our goal was to identify new molecular targets to improve the efficacy of hormonal therapy in breast cancer patients that have a poor response to hormonal therapy, in part, due to high circulating levels of unbound insulinIGF-1. Methods IGF-1-mediated effects on cytostasis and apoptotic cell death were determined with cell counts conducted in the presence and absence of trypan blue; enzyme-linked immunosorbent assays to determine the intracellular levels of cleaved cytokeratin 18, a marker of epithelial cancer cell apoptosis; and immunoblot analysis to determine the levels of cleaved poly-ADP ribose polymerase (PARP) and lamin A that result from caspase-dependent apoptosis. Cytotoxicity was further characterized by determination of the levels of reactive oxygen species (ROS) and the percent of mitochondrial membrane depolarization in cell populations treated with the different hormones in the presence and absence of IGF-1. Small molecule inhibitors of the dual-specificity protein kinase MEK1, MEK1 siRNA, Bim siRNA, and vectors overexpressing MEK1 wild type and mutant, dominant negative cDNA were used to identify key IGF-1 downstream prosurvival effectors. Results IGF-1, at physiologically relevant levels, blocked the cytotoxic action(s) of the antiestrogens 4-hydroxytamoxifen (4-OHT) and tamoxifen (TAM) when used as single agents or in combination with the antiprogestin MIF. The antiapoptotic action of IGF-1 was mediated primarily through the action of MEK1. MEK1 expression reduced the levels of ROS and mitochondrial membrane depolarization induced by the hormonal treatments via a mechanism that involved the phosphorylation and proteasomal turnover of the proapoptotic BH3-only Bcl-2 family member Bim. Importantly, small-molecule inhibitors of MEK1 circumvented the prosurvival action of IGF-1 by restoring Bim to levels that more effectively mediated apoptosis in ER + breast cancer cells. Conclusion his study provides strong support for the use of MEK1 inhibitors in combination with hormonal therapy to effectively affect cytostasis and activate a Bim-dependent apoptotic pathway in ER + breast cancer cells. We discuss that MEK1 blockade may be a particularly effective treatment for women with high circulating levels of IGF-1, which have been correlated to a poor prognosis.

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Breast cancer in postmenopausal women: what is the real risk?

Cited by 2 publications

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P53 Gene: Mutation and Immunohistochemical Analysis in Patients With Invasive Ductal Carcinoma of Breast

P53 Gene: Mutation and Immunohistochemical Analysis in Patients With Invasive Ductal Carcinoma of Breast

Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim

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