Three Loci Modify Growth of a Transgene-Induced Mammary Tumor: Suppression of Proliferation Associated with Decreased Microvessel Density

Voyer, Tom Le; Rouse, Jessica; Lu, Zuliang; Lifsted, Traci; Williams, Max; Hunter, Kent W.

doi:10.1006/geno.2001.6562

Cited by 40 publications

(26 citation statements)

References 27 publications

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“…Angiogenesis within human mammary tumors has been correlated with metastatic disease, and poor prognosis (33). Polyoma middle T-induced tumors have been shown to be poorly perfused in relationship to their growth (34), and yet tumor growth in this model has been shown to be influenced by the ability of the tumor to recruit microvessels (35). The dramatic reduction in microvessels seen in the pMT+/À TKÀ/À tumors compared with the pMT+/À TK+/+ tumors, coupled with their reduced growth rate, suggests that Ron signaling may play a role in promoting angiogenesis in this mammary tumor.…”

Section: Discussionmentioning

confidence: 99%

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Peace¹,

Toney-Earley²,

Collins

et al. 2005

Cancer Research

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The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TKÀ/À) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/À TK+/+) and pMT+/À TKÀ/À mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/À TKÀ/À mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labelingpositive staining in mammary tumor cells from the pMT+/À TKÀ/À mice compared with the pMT+/À TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TKÀ/À tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TKÀ/À tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT. (Cancer Res 2005; 65(4): 1285-93)

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Section: Discussionmentioning

confidence: 99%

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Peace¹,

Toney-Earley²,

Collins

et al. 2005

Cancer Research

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“…Interestingly, the Emca1 interval is supported by the fact that certain experimental condion RNO5 is syntenic to a region of mouse chromosome tions inhibit the rapid development of E2-induced mam-4 containing Mmtg2, a locus that modulated mouse polymary cancer but have no impact on sensitivity to E2-oma middle T-antigen-induced mammary tumor mass induced pituitary tumorigenesis (Shull et al 1997; but not latency in a cross between the I/LnJ and FVB / Harvell et al 2001). For example, ovariectomy inhib-N-TgN(MMTVPyMT) 634Mul strain (Le Voyer et al 2001). ited the rapid development of mammary cancers in ACI It has been postulated that E2-induced mammary carfemales treated with E2 for 20 weeks, but had no impact cinogenesis is dependent upon E2-induced pituitary tuon sensitivity to E2-induced pituitary tumorigenesis in morigenesis and associated hyperprolactinemia (Stone these same rats (Shull et al 1997).…”

Section: Cdkn2amentioning

confidence: 99%

Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat

et al. 2004

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Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17␤-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI ϫ COP)F 2 and (COP ϫ ACI)F 2 populations, we find strong evidence for a major genetic determinant of susceptibility to E2-induced mammary cancer on distal rat chromosome 5. Our data are most consistent with a model in which the ACI allele of this locus, termed Emca1 (e strogen-induced m ammary ca ncer 1), acts in an incompletely dominant manner to increase both tumor incidence and tumor multiplicity as well as to reduce tumor latency in these populations. We also find evidence suggestive of a second locus, Emca2, on chromosome 18 in the (ACI ϫ COP)F 2 population. The ACI allele of Emca2 acts in a dominant manner to increase incidence and decrease latency. Together, Emca1 and Emca2 act independently to modify susceptibility to E2-induced mammary cancer.

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“…15,16 Expression of the polyoma middle T-antigen oncogene has also been used to identify tyrosine kinase signaling pathways that alter mammary tumor latency. [17][18][19][20][21] In addition to predisposing women to breast cancer when mutated in the germline, somatic mutation or loss of the p53 tumor suppressor gene is a common feature of breast cancer. Therefore, we used Trp53 ϩ/Ϫ mice as a model system to identify genes that modify breast cancer susceptibility and may be relevant to both hereditary and sporadic breast cancer.…”

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confidence: 99%

Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk

Blackburn

Hill

Roberts

et al. 2007

The American Journal of Pathology

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Low-penetrance breast cancer susceptibility alleles seem to play a significant role in breast cancer risk but are difficult to identify in human cohorts. A genetic screen of 176 N2 backcross progeny of two Trp53 ؉/؊ strains, BALB/c and C57BL/6, which differ in their susceptibility to mammary tumors, identified a modifier of mammary tumor susceptibility in an ϳ25-Mb interval on mouse chromosome 7 (designated SuprMam1). Relative to heterozygotes, homozygosity for BALB/c alleles of SuprMam1 significantly decreased mammary tumor latency from 70.7 to 61.1 weeks and increased risk twofold (P ‫؍‬ 0.002). Dmbt1 (deleted in malignant brain tumors 1) was identified as a candidate modifier gene within the SuprMam1 interval because it was differentially expressed in mammary tissues from BALB/c-Trp53

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Three Loci Modify Growth of a Transgene-Induced Mammary Tumor: Suppression of Proliferation Associated with Decreased Microvessel Density

Cited by 40 publications

References 27 publications

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Ron Receptor Signaling Augments Mammary Tumor Formation and Metastasis in a Murine Model of Breast Cancer

Genetic Determination of Susceptibility to Estrogen-Induced Mammary Cancer in the ACI Rat

Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk

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