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      Mouse models of estrogen receptor-positive breast cancer

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          Abstract

          Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 – 70% of breast cancers are Estrogen Receptor alpha (ER-α) positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs) have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

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          Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.

          Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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            Tumor spectrum analysis in p53-mutant mice.

            The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis. In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele. We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.
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              Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome.

              We have asked whether oncogenesis by the mouse mammary tumor virus (MMTV), a slowly oncogenic retrovirus, involves integration of viral DNA within a certain region of the host genome. We first identified a C3H mouse mammary tumor bearing a single new MMTV provirus and cloned a 19 kilobase (kb) DNA restriction fragment containing a junction of viral and host sequences. Host sequences from this clone were used to retrieve 25 kb of the uninterrupted locus (termed MMTV int1) from a bacteriophage library of normal mouse DNA. Hybridization with subcloned DNA fragments of MMTV int1 detected abnormal restriction fragments in digests of DNA from 18 of 26 C3H mammary tumors. The rearrangements all appeared to be due to the insertion of an MMTV provirus, and the integration sites were located in at least five clusters over a total distance of 19 kb. A polyadenylated 2.6 kb RNA species transcribed from int1 was found in the few tumors tested, but not in lactating mammary glands from C3H mice. Of 12 tested viral oncogenes, none exhibited homology with cloned DNA from this locus. We propose that tumorigenesis by MMTV is strongly favored by proviral insertion within the int1 locus, perhaps as a consequence of enhanced expression of a novel cellular oncogene.
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                Author and article information

                Journal
                J Carcinog
                JC
                Journal of Carcinogenesis
                Medknow Publications & Media Pvt Ltd (India )
                0974-6773
                1477-3163
                2011
                22 December 2011
                : 10
                : 35
                Affiliations
                [1 ]Department of Genetics, Cell Biology, and Anatomy, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
                [2 ]Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
                [3 ]Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
                [4 ]Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
                [5 ]The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
                Author notes
                [* ]Corresponding author
                Article
                JC-10-35
                10.4103/1477-3163.91116
                3263010
                22279420
                eea69335-7718-48fa-9881-4736faca7c15
                © 2011 Mohibi

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 September 2011
                : 20 October 2011
                Categories
                Review Article

                Oncology & Radiotherapy
                breast cancer,mouse models,estrogen receptor-α
                Oncology & Radiotherapy
                breast cancer, mouse models, estrogen receptor-α

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