Abstract 3424: Role of miR-489 in mammary gland development and Her2 mediated tumorigenesis
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Abstract HER2 overexpression is linked with poor prognosis and outcome in breast cancer. In our previous study, we have found miR-489 was specifically down regulated by HER2 overexpression. Restoration of miR-489 in multiple breast cancer cell lines significantly inhibited cell growth in vitro and decreased tumor growth in xenograft mice. To study role of miR-489 in Her2 mediated tumorigenesis, for the first time we generated MMTV-miR-489 transgenic mice, which overexpress miR-489 specifically in mammary gland. Our qRT-PCR data has confirmed transgenic mice have significantly more miR-489 expression than FVB mice. We used western blot to further validate our model system and found significant downregulation of miR-489 targets DEK and PTPN11. To find out whether miR-489 has any role in mammary gland development, mammary gland whole mount was performed from wild type FVB mice and MMTV-miR-489 mice at different age. Mammary gland from MMTV-miR-489 mice demonstrated reduction in growth at early age. Our immunohistochemistry staining demonstrated significantly reduction in Ki-67 positive cells in MMTV-miR-489 mammary gland at early age, further confirming reduced growth in MMTV-miR-489 mice. However, we found no significant effect on weight of litters of MMTV-miR-489 female since after 8-week mammary gland was able to recover growth. To find out effect of miR-489 overexpression on Her2 mediated tumorigenesis, we generated double transgenic mice MMTV-Her2/miR-489 by crossing MMTV-miR-489 mice with MMTV-Her2 mice. We have observed significant delay in tumor onset and reduced tumor growth in MMTV-Her2/ miR-489 mice compare to MMTV-Her2 mice. We have also observed less number of metastatic site in lung by performing H and E staining of lung. Our IHC data showed reduction in PTPN11 and DEK in miR-489 overexpress mammary tumor. Surprisingly, we found significant reduction of miR-489 expression in mammary tumors of MMTV-Her2-miR-489 when compared with normal mammary gland of same mice. Overall, our results indicated miR-489 overexpression suppresses mammary gland development at early age, reduced mammary tumorigenesis and decrease lung metastasis by targeting PTPN11 and DEK. Citation Format: Yogin Patel, Mithil Soni, Shou Liu, Hexin Chen. Role of miR-489 in mammary gland development and Her2 mediated tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3424. doi:10.1158/1538-7445.AM2017-3424Keywords:
Mammary tumor
Large amounts of murine mammary tumor virus (MMTV) were expressed in milk from a low mammary tumor mouse strain called II-TES, established by crossbreeding DBA/2 mouse strain with two strains of Japanese pet mouse origin. The reciprocal hybrids of the II-TES strain and OZ-F strain, another low mammary tumor strain of Japanese pet mouse origin, developed early-appearing mammary tumors at a high rate, and large quantities of MMTV were expressed in the milk. These findings suggest that different regulatory genes control MMTV expression and mammary tumorigenesis.
Mammary tumor
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Ratón
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We generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the beta-actin locus. Mice that are hemizygous for this transgene express normal levels of beta-actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorie-restricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity.
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Occurrence of spontaneous tumor in experimental animals is of great concern in long-term carcinogenic and chronic toxicity studies. Among spontaneous tumors, mammary tumor is one of the most predominant tumor in mice. However, it is well known that mouse mammary tumor virus (MMTV) is widely involved in all cells in the mice in a proviral form. Based on endogenous viral gene patterns, all strains of mice including inbred or non-inbred carried 2-6 such genes, though the incidence of mammary tumor is different depending on the strains. Administration of urethane in the drinking water of breeding mice lead to a higher incidence of mammary tumor at an early age in these strains. Urethane, however, did not induce or enhance endogenous retroviral antigen expression or increase in MMTV-DNA sequences in mammary tumor by radioimmunoassay or molecular hybridization. These results showed that MMTV was not involved in chemical carcinogenesis of the mouse mammary glands. In regard to mammary tumors in carcinogenic or chronic toxicity studies, we must examine further whether endogenous MMTV is activated or not.
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To characterize the role of BRCA1 in mammary gland development and tumor suppression, a transgenic mouse model of BRCA1 overexpression was developed. Using the mouse mammary tumor virus (MMTV) promoter/enhancer, transgenic mice expressing human BRCA1 or select mutant controls were generated. Transgenic animals examined during adolescence were shown to express the human transgene in their mammary glands. The mammary glands of 13-week-old virgin homozygous MMTV-BRCA1 mice presented the morphology of moderately increased lobulo-alveolar development. The mammary ductal trees of both hemizygous and homozygous MMTV-BRCA1t340 were similar to those of control non-transgenic littermates. Interestingly, both hemi- and homozygous mice expressing a splice variant of BRCA1 lacking the N-terminal RING finger domain (MMTV-BRCA1sv) exhibited marked mammary lobulo-alveolar development, particularly terminal end bud proliferation. Morphometric analyses of mammary gland whole mount preparations were used to measure epithelial staining indices of ~35% for homozygous MMTV-BRCA1 mice and ~60% for both hemizygous and homozygous MMTV-BRCA1sv mice versus ~25% for non-transgenic mice. Homozygous MMTV-BRCA1 mice showed delayed development of tumors when challenged with 7,12 dimethylbenzanthracene (DMBA), relative to non-transgenic and homozygous BRCA1t340 expressing mice. In contrast, homozygous MMTV-BRCA1sv transgenic animals were sensitized to DMBA treatment and exhibited a very rapid onset of mammary tumor development and accelerated mortality. MMTV-BRCA1 effects on mortality were restricted to DMBA-induced tumors of the mammary gland. These results demonstrate in vivo roles for BRCA1 in both mammary gland development and in tumor suppression against mutagen-induced mammary gland neoplasia.
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What are transgenic mice and what do we learn from them? In this review, we focus on the generation of "classical" transgenic and "knock-out" mice. The establishment of transgenic and gene-targeted mice provides an unique tool to study the function(s) of a given gene in the context of a whole organism. Based on selected examples, we demonstrate the potential of this transgenic technology to understand the interactions between cells, organs and organ systems in genetically engineered mice.
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Transgenic mice have had a tremendous impact on biomedical research. Most researchers are familiar with transgenic mice that carry Cre recombinase (Cre) and how they are used to create conditional knockouts. However, some researchers are less familiar with many of the other types of transgenic mice and their applications. For example, transgenic mice can be used to study biochemical and molecular pathways in primary cultures and cell suspensions derived from transgenic mice, cell-cell interactions using multiple fluorescent proteins in the same mouse, and the cell cycle in real time and in the whole animal, and they can be used to perform deep tissue imaging in the whole animal, follow cell lineage during development and disease, and isolate large quantities of a pure cell type directly from organs. These novel transgenic mice and their applications provide the means for studying of molecular and biochemical events in the whole animal that was previously limited to cell cultures. In conclusion, transgenic mice are not just for generating knockouts.
Gene knockout
Cre recombinase
Knockout mouse
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Conditional gene knockout
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The mammary gland is the most promising target tissue because it produces large amounts of recombinant human proteins, enzymes, hormones and growth factors in a temperature-regulated fluid that may be collected daily, in a non-invasive fashion. Different observations and conclusions have been made concerning the development, histology and ultrastructure of transgenic mammary epithelium. Therefore, there is a necessity to examine possible histological and ultrastructural changes in transgenic rabbit mammary gland tissue. This review summarizes recent results based on the analyses of transgenic rabbit mammary gland at different developmental stages over four generations of transgenic animals.
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