[DOWNLOAD] "Use of a Transgenic Mouse Model of Ovarian Hyperstiumluation to Identify Therapeutic Targets and Mechanisms in Hormone-Induced Mammary Cancer" by Erin L. Milliken # eBook PDF Kindle ePub Free
eBook details
- Title: Use of a Transgenic Mouse Model of Ovarian Hyperstiumluation to Identify Therapeutic Targets and Mechanisms in Hormone-Induced Mammary Cancer
- Author : Erin L. Milliken
- Release Date : January 19, 2013
- Genre: Medical,Books,Professional & Technical,Science & Nature,Engineering,
- Pages : * pages
- Size : 21429 KB
Description
Epidemiological studies and clinical trials have revealed the critical impact that reproductive hormones have on breast cancer. The work described in this dissertation characterizes a transgenic mouse model, the LH-overexpressing mouse, which develops mammary gland hyperplasia and tumorigenesis in response to ovarian hyperstimulation, making it a unique model of hormone-induced mammarycancer. The hyperplasia in these mice is ovary-dependent and is due to a dramatic increase in proliferation of mammary epithelial cells. Most of the spontaneous mammary tumors that form in this model are mammary intraepithelial neoplasias that lack expression of both estrogen and progesterone receptors. The LH-overexpressing mice have been utilized to investigate potential therapeutic targets and identify mechanisms that contribute to hormone-mediated mammary gland pathology. Similar to observations made in human breast cancer, the pre-neoplastic mammary glands and tumors of LH-overexpressing mice demonstrate increased expression of vitamin D receptor, supporting the notion that this protein is a potential target for therapy. Treatment with EB1089, a vitamin D receptor agonist, results in decreased proliferation in the pre-neoplastic mammary glands of LH-overexpressing mice and reduces the growth rate of a subset of established mammary tumors, providing evidence for both chemopreventive and chemotherapeutic benefits of activating the vitamin D receptor. Analysis of pre-neoplastic mammary glands of LH-overexpressing mice has revealed the presence of centrosome amplification, suggesting that genomic instability may contribute to hormone-induced mammary tumorigenesis. Although centrosome amplification and genomic instability in human cancers are often associated with mutations in the p53 protein, the p53 sequence is intact in mammary tumors of LH-overexpressing mice. Furthermore, p53 is capable of being functionally activated in the mammary glands of transgenic mice in response to ionizing radiation, as evidenced by increased phosphorylation, upregulation of target genes, and induction of apoptosis. Along with the fact that introduction of a mutant form of p53 does not alter tumor latency, these data suggest that hormone-induced mammary tumors is not dependent on direct perturbation of the p53 signaling pathway. Future studies using the LH-overexpressing mouse should provide further insight into both potential therapeutic targets for treatment of hormone-induced mammary cancer and the mechanisms through which this disease progresses.
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