The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting

Cardiff, Robert D.; Anver, Miriam R.; Gusterson, Barry A.; Hennighausen, Lothar; Jensen, Roy A.; Merino, María J.; Rehm, Sabine; Russo, José; Tavassoli, Fattaneh A.; Wakefield, Lalage M.; Ward, Jerrold M.; Green, Jeffrey E.

doi:10.1038/sj.onc.1203277

Cited by 456 publications

(419 citation statements)

References 53 publications

(41 reference statements)

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“…Of the 13 WAP-DES mice analysed, eight (62%) had microadenomas ( Figure 2c). All of the WAP-DES mice demonstrated either low grade (Figure 2b) or high grade mammary interepithelial neoplasia (MIN) as recently de®ned by an NIH-sponsored meeting on the pathology of genetically engineered mice (Cardi et al, 2000). Of the mice bearing palpable tumors, all exhibited MIN lesions similar to those in Figure 2.…”

Section: Mammary Tumorigenesis In the Wap-des Micementioning

confidence: 64%

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

et al. 2000

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Mammary tumorigenesis was analysed in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53 172R-H ). Nonlactating, multiparous WAP-DES mice exhibited hyperplastic lesions termed mammary interepithelial neoplasia (MIN) which constitutively expressed WAP-DES. By 23 months of age, 53% of the WAP-DES mice developed mammary adenocarcinomas. A 75% reduction in both apoptosis and proliferation was observed in the normal mammary glands of WAP-DES mice. Mammary tumor incidence in WAP-DES/p53 bitransgenic mice was similar to that of WAP-DES and 2 ± 3-fold greater than that of nontransgenic and p53 172R-H females. Tumor latency, however, was reduced by 8 months in bitransgenic mice as compared to mice of the other three genotypes. Aneuploidy was frequently observed in tumors from bitransgenic and p53 172R-H mice, but not from mice expressing only the WAP-DES transgene. Expression of IGFBP3 was elevated in tumors from WAP-DES, but not bitransgenic mice, indicating an alteration in the p53/IGF-I axis. These studies indicate that overexpression of des(1-3)hIGF-I increases the frequency of MIN and stochastic mammary tumors and that the appearance of tumors displaying genomic instability is accelerated by mutant p53 172R-H . Oncogene (2000) 19, 889 ± 898.

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Section: Mammary Tumorigenesis In the Wap-des Micementioning

confidence: 64%

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

et al. 2000

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“…44 For a careful examination of metastatic spread to lungs, all lobes of every lung were evaluated on a single histological section. The effect of therapies on metastases was expressed as percentage of mice carrying lung metastases with respect to the total number of mice analyzed in every group.…”

Section: Animals and Pathological Examinationmentioning

confidence: 99%

Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer

et al. 2003

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Treatments available to women with locally advanced breast cancer are unsatisfactory, since most patients succumb to metastatic spread. Therefore, there is a need to devise novel therapeutic combinations that effectively inhibit metastatization and to test them in animal models of breast cancer showing strong similarities with their human counterpart, including the ability to give rise to metastases. With these considerations in mind, tamoxifen (TAM), 4-hydrotamoxifen (4-HT) or liposome-complexed DNA constructs coding for antiangiogenic/anti-invasion proteins (angiostatin, TIMP-2, IFN-a 1 , sFLT-1) were individually administered to MMTVneu transgenic mice. Significant inhibition of primary tumor growth was obtained with TAM (40% inhibition, P¼0.049), angiostatin (85% inhibition, P¼0.001) and TIMP-2 (60% inhibition, P¼0.015). No lung metastasis was observed in any of these treated mice at 5 months, compared with a rate of 70% in control groups. These observations were the basis for designing a combined treatment with all these compounds. The association of angiostatin, TIMP-2 and TAM was greatly effective at the primary tumor level (90% inhibition, P¼0.01). Moreover, all the mice treated with this association were metastasis free at a time point (6 months) in which seven out of nine control mice were either dead from disseminated cancer or showed lung metastasis. This combined therapy could become an important component of anticancer therapy in humans.

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“…Sections were cut at 5 m, stained with hematoxylin and eosin, and evaluated by an experienced histopathologist. Analyses and descriptions were performed in accordance with the guidelines put forth by the mammary gland pathology consensus meeting in Annapolis (Cardiff et al, 2000). …”

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confidence: 99%

Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice

Williams

Cheung

Park

et al. 2003

MBoC

136

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Caveolin-1 is the principal structural component of caveolae microdomains, which represent a subcompartment of the plasma membrane. Several independent lines of evidence support the notion that caveolin-1 functions as a suppressor of cell transformation. For example, the human CAV-1 gene maps to a suspected tumor suppressor locus (D7S522/7q31.1) that is frequently deleted in a number of carcinomas, including breast cancers. In addition, up to 16% of human breast cancers harbor a dominant-negative mutation, P132L, in the CAV-1 gene. Despite these genetic associations, the tumor suppressor role of caveolin-1 still remains controversial. To directly assess the in vivo transformation suppressor activity of the caveolin-1 gene, we interbred Cav-1 (Ϫ/Ϫ) null mice with tumor-prone transgenic mice (MMTV-PyMT) that normally develop multifocal dysplastic lesions throughout the entire mammary tree. Herein, we show that loss of caveolin-1 gene expression dramatically accelerates the development of these multifocal dysplastic mammary lesions. At 3 wk of age, loss of caveolin-1 resulted in an approximately twofold increase in the number of lesions (foci per gland; 3.3 Ϯ 1.0 vs. 7.0 Ϯ 1.2) and an approximately fiveto sixfold increase in the total area occupied by these lesions. Similar results were obtained at 4 wk of age. However, complete loss of caveolin-1 was required to accelerate the appearance of these dysplastic mammary lesions, because Cav-1 (ϩ/Ϫ) heterozygous mice did not show any increases in foci development. We also show that loss of caveolin-1 increases the extent and the histological grade of these mammary lesions and facilitates the development of papillary projections in the mammary ducts. Finally, we demonstrate that cyclin D1 expression levels are dramatically elevated in Cav-1 (Ϫ/Ϫ) null mammary lesions, consistent with the accelerated appearance and growth of these dysplastic foci. This is the first in vivo demonstration that caveolin-1 can function as a transformation suppressor gene. INTRODUCTIONCaveolae are 50 -100-nm plasma membrane microdomains that function in vesicular trafficking and signal transduction (Galbiati et al., 2001). Approximately 10 years ago, the principal structural component of caveolae was identified as a 21-to 24-kDa integral membrane protein and termed caveolin (Glenney and Zokas, 1989;Rothberg et al., 1992) (now referred to as caveolin-1) (Scherer et al., 1996).Caveolin-1 is expressed in numerous cell types, including fibroblasts, adipocytes, smooth muscle cells, endothelial cells, and epithelial cells . Interestingly, caveolin-1 was first described as a major substrate of the DOI: 10.1091/mbc.E02-08 -0503.¶ Corresponding author. E-mail address: lisanti@aecom.yu.edu. © 2003 by The American Society for Cell Biology 1027v-Src tyrosine kinase in Rous sarcoma virus-transformed fibroblasts, suggesting that caveolin-1 may be a target for modification or inactivation by activated oncogenes . Subsequent cell culture experiments demonstrated that caveolin-1 mRNA and protein expression lev...

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The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting

Cited by 456 publications

References 53 publications

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer

Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice

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