The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

Ricciardelli, Carmela; Frewin, Kate; Tan, Izza de Arao; Williams, Elizabeth D.; Opeskin, Kenneth; Pritchard, Melanie April; Ingman, Wendy V.; Russell, Darryl L.

doi:10.1016/j.ajpath.2011.08.021

Cited by 70 publications

(92 citation statements)

References 57 publications

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“…Adamts1 has been ablated in the MMTV-PyMT mouse model previously, revealing the requirement for Adamts1 during tumor metastasis (55). Importantly, that work demonstrated that Adamts1 remodels the ECM to facilitate the transition from ductal carcinoma in situ to invasive and metastatic disease.…”

Section: Discussionmentioning

confidence: 80%

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

112

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bWhile the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control. Breast cancer remains a leading cause of death for women, with high mortality rates attributed to distant metastasis (1). To simplify the examination of signaling pathway requirements in metastatic breast cancer, research has turned to mouse model systems. Previous studies with mouse models of breast cancer have begun to reveal the mechanistic features of breast cancer metastasis, and in vivo selection has demonstrated the ability to select for tumors that metastasize to a specific location (2-5). Yet we lack a complete understanding of the pathways that govern the molecular circuitry of metastatic breast cancer. One model that has been integral in examining metastatic progression is the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) model. Originally described as exhibiting rapid tumor onset and a high degree of pulmonary metastasis (6), this model has since been used to examine a number of facets of metastasis. For example, work using the MMTV-PyMT model led to the discovery of the prometastatic signaling exchange between tumors and macrophages (7). In addition, the metastatic contributions of individual signaling molecules, such as transforming growth factor ␤ (TGF-␤), AKT, and adiponectin, have also been uncovered using this model (8-10). Given that PyMT can activate multiple signaling pathways with relevance to human breast cancer (11), there is clear utility in this model for characterizing pathways that contribute to breast cancer metastasis.The identification of signaling pathways contributing to tumor progression has bee...

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Section: Discussionmentioning

confidence: 80%

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

Hollern

Honeysett

Cardiff

et al. 2014

Molecular and Cellular Biology

112

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“…By extension to the role of Egfr/Ras in tumors this would be considered a tumor suppressor function. Interestingly, there is also a connection to the Egfr pathway in mammals where ADAMTS1 acts as an activator by promoting the shedding of heparin-binding EGF ligands (Liu et al 2006(Liu et al , 2009Ricciardelli et al 2011). In contrast, and in keeping with the inhibitory function of CG4096, it has also been suggested that a self-cleaved product of ADAMTS1 could act as a repressor by sequestering ligands (Liu et al 2006).…”

Section: Discussionmentioning

confidence: 99%

New Negative Feedback Regulators of Egfr Signaling inDrosophila

et al. 2012

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The highly conserved epidermal growth factor receptor (Egfr) pathway is required in all animals for normal development and homeostasis; consequently, aberrant Egfr signaling is implicated in a number of diseases. Genetic analysis of Drosophila melanogaster Egfr has contributed significantly to understanding this conserved pathway and led to the discovery of new components and targets. Here we used microarray analysis of third instar wing discs, in which Egfr signaling was perturbed, to identify new Egfrresponsive genes. Upregulated transcripts included five known targets, suggesting the approach was valid. We investigated the function of 29 previously uncharacterized genes, which had pronounced responses. The Egfr pathway is important for wing-vein patterning and using reverse genetic analysis we identified five genes that showed venation defects. Three of these genes are expressed in vein primordia and all showed transcriptional changes in response to altered Egfr activity consistent with being targets of the pathway. Genetic interactions with Egfr further linked two of the genes, Sulfated (Sulf1), an endosulfatase gene, and CG4096, an A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS) gene, to the pathway. Sulf1 showed a strong genetic interaction with the neuregulin-like ligand vein (vn) and may influence binding of Vn to heparan-sulfated proteoglycans (HSPGs). How Drosophila Egfr activity is modulated by CG4096 is unknown, but interestingly vertebrate EGF ligands are regulated by a related ADAMTS protein. We suggest Sulf1 and CG4096 are negative feedback regulators of Egfr signaling that function in the extracellular space to influence ligand activity.

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“…Furthermore, the ECM protease ADAMTS1 is important for ovulation [22,23] and is predominantly sequestered in its active form in the COC matrix [24]. Active ADAMTS1 has been established to play a role during invasive cancer metastasis in other tissues [25][26][27][28]. Thus, the expanded COC matrix may be conducive to invasive migration of cumulus cells.…”

Section: Introductionmentioning

confidence: 97%

Transient Invasive Migration in Mouse Cumulus Oocyte Complexes Induced at Ovulation by Luteinizing Hormone1

Akison

Alvino

Dunning

et al. 2012

Biology of Reproduction

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Ovulation, the release of the oocyte from the ovarian follicle, is initiated by the luteinizing hormone surge. It is clear that highly controlled degradation of the follicle and ovarian wall is required for passage of the oocyte and accompanying cumulus cells from the follicle, but the mechanism has not yet been elucidated. Here we show that cumulus oocyte complexes (COCs) adopt transient adhesive, migratory, and matrix-invading capacities at the time of ovulation. We characterized cell adhesion, migration, and invasion in preovulatory and postovulatory mouse COCs collected over a time course post-human chorionic gonadotropin (hCG) administration. Adhesion of dispersed cumulus cells and intact COCs to extracellular matrix proteins present in the ovarian wall (collagens, laminin, and fibronectin) increased significantly after hCG treatment and declined immediately after ovulation. Cumulus cell migration was low in unexpanded, equine chorionic gonadotropin-only treated COCs, but increased 4, 8, and 10 h post-hCG, reaching a peak at 12 h post-hCG that coincided with ovulation. The ability of cumulus cells to migrate was rapidly diminished in COCs isolated from the oviduct within 2 h postovulation. Cell migration was cumulus cell specific and was not observed in granulosa cells. Invasion through three-dimensional collagen I and matrigel barriers by preovulatory expanded COCs was equivalent to that of a known invasive breast cancer cell line (MB-231). Cumulatively, these results demonstrate that cumulus cells in the expanded COC transition to an adhesive, motile, and invasive phenotype in the periovulatory period that may be required for successful release of the oocyte from the ovary at ovulation.

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The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

Cited by 70 publications

References 57 publications

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

The E2F Transcription Factors Regulate Tumor Development and Metastasis in a Mouse Model of Metastatic Breast Cancer

New Negative Feedback Regulators of Egfr Signaling inDrosophila

Transient Invasive Migration in Mouse Cumulus Oocyte Complexes Induced at Ovulation by Luteinizing Hormone1

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