Transgenic mice with mammary gland targeted expression of human cortactin do not develop (pre-malignant) breast tumors: studies in MMTV-cortactin and MMTV-cortactin/-cyclin D1 bitransgenic mice

Rossum, Agnes G.S.H. van; Bragt, Maaike P.A. van; Schuuring-Scholtes, Ellen; Ploeg, Jan C M van der; Krieken, J. Han J.M. van; Kluin, Philip M.; Schuuring, Ed

doi:10.1186/1471-2407-6-58

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…We noticed a low incidence of similar pre‐cancerous lesions in Men1 F/F control mice. The fact that WapCre‐Men1 +/+ mouse littermates did not show a similar phenotype does not support the view that the mouse genetic background could be the factor causing the predisposition to MIN lesions as previously reported . Rather, although the floxed Men1 allele has previously been proven to be both functional and non‐hypomorphic , we cannot exclude the possibility that some unknown disturbance of the floxed Men1 allele could interfere with menin's function in mammary cells.…”

Section: Discussioncontrasting

confidence: 72%

High incidence of mammary intraepithelial neoplasia development in Men1‐disrupted murine mammary glands

Seigne

Auret

Treilleux

et al. 2013

The Journal of Pathology

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Mutations of the MEN1 tumour suppressor gene predispose patients to the development of multiple endocrine neoplasia type 1 (MEN1) syndrome, which is characterized by multiple endocrine tumours, including prolactinomas. The recent findings of the interaction between menin, encoded by the MEN1 gene, and the oestrogen receptor, as well as the observation of rare cases of mammary carcinomas in our heterozygous Men1 mutant mice, led us to investigate a putative tumour suppressor function of the Men1 gene in mouse mammary cells by disrupting the gene in luminal epithelial cells. A significantly higher incidence of mammary intraepithelial neoplasia (MIN) was observed in mutant WapCre-Men1(F/F) mice (51.5%) than in WapCre-Men1(+/+) (0%) or Men1(F/F) (7.1%) control mice. The majority of MIN observed in the mutant mice displayed complete menin inactivation. Because of the leakage of WapCre transgene expression, prolactinomas were observed in 83.3% of mutant mice, leading to premature death. As there was no correlation between MIN development and elevated serum prolactin levels, and phospho-STAT5 expression was decreased in mammary lesions, the increased incidence of MIN lesions was most likely due to Men1 disruption rather than to prolactinoma development. Interestingly, in MIN lesions, we found a decrease in membrane-associated E-cadherin and beta-catenin expression, the latter of which is a menin partner. Finally, reduced menin expression was found in a large proportion of two independent cohorts of patients with breast carcinomas. Taken together, the current work indicates a role of Men1 inactivation in the development of mammary pre-cancerous lesions in mice and a potential role in human mammary cancer.

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Section: Discussioncontrasting

confidence: 72%

High incidence of mammary intraepithelial neoplasia development in Men1‐disrupted murine mammary glands

Seigne

Auret

Treilleux

et al. 2013

The Journal of Pathology

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“…Unlike cyclin D1, transgenic expression of cortactin in the mouse mammary gland does not induce hyperplasias or tumors. 144 By contrast, overexpression of cortactin in established human carcinoma cell lines leads to aggressive in vivo behavior for multiple tumor types. In experimental metastasis assays, cortactin overexpression in breast and esophageal squamous carcinoma (ESCC) cells led to enhanced metastasis to the bone and lungs, respectively.…”

Section: Discussionmentioning

confidence: 95%

Cortactin

Kirkbride¹,

Sung²,

Sinha³

et al. 2011

Cell Adhesion & Migration

152

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Branched actin assembly is critical for a variety of cellular processes that underlie cell motility and invasion, including cellular protrusion formation and membrane trafficking. Activation of branched actin assembly occurs at various subcellular locations via site-specific activation of distinct WASp family proteins and the Arp2/3 complex. A key branched actin regulator that promotes cell motility and links signaling, cytoskeletal and membrane trafficking proteins is the Src kinase substrate and Arp2/3 binding protein cortactin. Due to its frequent overexpression in advanced, invasive cancers and its general role in regulating branched actin assembly at multiple cellular locations, cortactin has been the subject of intense study. Recent studies suggest that cortactin has a complex role in cellular migration and invasion, promoting both on-site actin polymerization and modulation of autocrine secretion. Diverse cellular activities may derive from the interaction of cortactin with site-specific binding partners.

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“…Considering their function in cell-matrix interaction, we speculate that overexpression of these three genes might contribute to the invasive potential of OSCC cells in patients with 11q13 amplification, while CCND1 overexpression may render OSCC cells a growth advantage. Recently, the 11q13 amplification was mimicked in mouse mammary gland tumors by generating MMTV-cortactin/ MMTV-cyclin D1 bitransgenic mice (van Rossum et al, 2006). However, no synergistic effect of cortactin on cyclin D1-induced mammary hyperplasia, carcinomas, or development of distant metastasis was observed, which suggests that either more genes in the 11q13 amplicon in addition to EMS1 may collaborate with CCND1 to promote tumorigenesis or there is another important yet unidentified gene or set of genes in the 11q13 amplicon.…”

Section: Discussionmentioning

confidence: 97%

Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma

Huang

Godfrey

Gooding

et al. 2006

Genes Chromosomes & Cancer

121

111

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11q13 amplification occurs in a wide variety of tumors, including almost half of oral squamous cell carcinomas (OSCC) where it has been correlated with a poor outcome. In this study, we compiled 3.6 Mb of DNA sequence in the 11q13 amplicon core and refined the physical map of the amplicon. In the process, we determined the genomic structure and normal tissue expression patterns of two recently identified genes, TAOS2/TMEM16A and MRGF, which reside in the amplicon core. We then quantified DNA copy number and mRNA expression of all genes in the 11q13 amplicon in cell lines and primary tumors from OSCC. With the exception of FGF3, FGF4, FGF19, and MRGF, all genes were overexpressed in most tumors with genomic amplification. Furthermore, we found that the expression of genes in the amplicon appeared to be highly coordinated, making it difficult to determine which gene or genes are driving amplification. However, in nonamplified primary tumors, three genes, TAOS2/TMEM16A, OCIM, and TPCN2, are frequently overexpressed, whereas CCND1 and EMS1 are not. These results suggest that in addition to CCND1 and EMS1, other important genes also may be target genes driving 11q13 amplification. We hypothesize that 11q13 amplification may be driven by a cassette of genes that provide growth or metastatic advantage to cancer cells. This is supported by the finding that the human 11q13 amplicon core is syntenic to mouse chromosomal band 7F5, which is frequently amplified in chemically induced murine OSCC. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat

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Transgenic mice with mammary gland targeted expression of human cortactin do not develop (pre-malignant) breast tumors: studies in MMTV-cortactin and MMTV-cortactin/-cyclin D1 bitransgenic mice

Cited by 13 publications

References 33 publications

High incidence of mammary intraepithelial neoplasia development in Men1‐disrupted murine mammary glands

High incidence of mammary intraepithelial neoplasia development in Men1‐disrupted murine mammary glands

Cortactin

Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma

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