Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

Berton, Thomas R.; Mutoh, T.; Page, Angustias; Conti, Claudio J.; Deng, Chu Xia; Jorcano, José L.; Johnson, D. Gale

doi:10.1038/sj.onc.1206825

Cited by 35 publications

(25 citation statements)

References 67 publications

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“…Moreover, Fanc/Brca pathway-associated genes are downregulated in sporadic HNSCC (6,35,45,46). Additionally, mice with epithelia-specific heterozygous knockout of Brca1 developed oral SCCs, indicating that Brca1 loss plays an important role in HNSCC tumorigenesis (47). In the current study, downregulation of Fanc/Brca pathway genes was detected in both grossly normal buccal mucosa and HNSCC lesions of HN-Smad4 -/-mice.…”

Section: Figuresupporting

confidence: 57%

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

et al. 2009

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Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4 -/-mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

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Section: Figuresupporting

confidence: 57%

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

et al. 2009

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“…26), and K5Cre (FVB background) mice were a gift from D.G. Johnson (University of Texas MD Anderson Cancer Center, Smithville, Texas, USA) (25). Animal protocols and usage were approved by the University of Rochester Committee on Animal Resources, and the mice were kept in a specific pathogen-free environment at the animal facility of the University of Rochester.…”

Section: Methodsmentioning

confidence: 99%

Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression

Lai¹,

Lai²,

Chuang³

et al. 2009

J. Clin. Invest.

184

188

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Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte-and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-α expression. Furthermore, AR enhanced local TNF-α expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-α expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing.

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“…To extend the testing of Edn2 overexpression to later times and additional tissues, we examined the vasculature in Z/Edn2; K5-Cre and Z/Edn2;Foxg1-Cre mice, in which Cre production begins at or shortly after midgestation in the epidermis (33) and before midgestation in the head, respectively (34). Sections of postnatal skin from Z/Edn2;K5-Cre mice and late-gestation brains from Z/Edn2;Foxg1-Cre fetuses show vascular architecture indistinguishable from normal littermate controls (Figs.…”

Section: Tissue and Developmental Stage Specificity Of The Antiangiogmentioning

confidence: 99%

Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Rattner

Williams

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here, we report that constitutive overexpression of Endothelin-2 (Edn2) in the mouse retina perturbs vascular development by inhibiting endothelial cell migration across the retinal surface and subsequent endothelial cell invasion into the retina. Developing endothelial cells exist in one of two states: tip cells at the growing front and stalk cells in the vascular plexus behind the front. This division of endothelial cell states is one of the central organizing principles of angiogenesis. In the developing retina, Edn2 overexpression leads to overproduction of endothelial tip cells by both morphologic and molecular criteria. Spatially localized overexpression of Edn2 produces a correspondingly localized endothelial response. Edn2 overexpression in the early embryo inhibits vascular development at midgestation, but Edn2 overexpression in developing skin and brain has no discernible effect on vascular structure. Inhibition of retinal angiogenesis by Edn2 requires expression of Endothelin receptor A but not Endothelin receptor B in the neural retina. Taken together, these observations imply that the neural retina responds to Edn2 by synthesizing one or more factors that promote the endothelial tip cell state and inhibit angiogenesis. The response to Edn2 is sufficiently potent that it overrides the activities of other homeostatic regulators of angiogenesis, such as Vegf.

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Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues

Cited by 35 publications

References 67 publications

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression

Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

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