Ectopic Runx2 Expression in Mammary Epithelial Cells Disrupts Formation of Normal Acini Structure: Implications for Breast Cancer Progression

Pratap, Jitesh; Imbalzano, Karen M.; Underwood, Jean M.; Cohet, Nathalie; Gokul, Karthiga Devi; Akech, Jacqueline; Wijnen, André J. van; Stein, Janet L.; Imbalzano, Anthony N.; Nickerson, Jeffrey A.; Lian, Jane B.; Stein, Gary S.

doi:10.1158/0008-5472.can-09-1471

Cited by 80 publications

(118 citation statements)

References 42 publications

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“…Our finding that RUNX2 may have functions in cell adhesion and motility of mobile osteosarcoma cells complements earlier findings obtained with both loss-of function and gain-of-function experiments in murine models (e.g. Runx2 null mouse embryonic fibroblasts and murine T cell lymphoma cells (14 -18)), as well as human breast and prostate cancer cells (45)(46)(47)(75)(76)(77)(78).…”

Section: Journal Of Biological Chemistry 4513supporting

confidence: 89%

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

Deen

Akech

Lapointe

et al. 2012

Journal of Biological Chemistry

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Background:The osteogenic Runt-related (RUNX) transcription factor Runx2 is frequently elevated in osseous and nonosseous tumor cells. Results: Genomic RUNX2 target genes involved in motility were identified; RUNX2 depletion reduces cell motility in osteosarcoma cells. Conclusion: RUNX2 regulates cell motility and adhesion in osteosarcoma cells. Significance: RUNX2 may also control migration of normal osteoblasts and/or tumor cells.

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Section: Journal Of Biological Chemistry 4513supporting

confidence: 89%

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

Deen

Akech

Lapointe

et al. 2012

Journal of Biological Chemistry

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“…[6][7][8][9] Recent studies demonstrate that Runx2 is also expressed in many cancer cells, 15,[43][44][45][46][47] including myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

Myeloma cell–derived Runx2 promotes myeloma progression in bone

Trotter

Pan

et al. 2015

Blood

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• Myeloma cell-derived Runx2 promotes myeloma progression.• High levels of Runx2 expression are associated with a high-risk myeloma population.The progression of multiple myeloma (MM) is governed by a network of molecular signals, the majority of which remain to be identified. Recent studies suggest that Runt-related transcription factor 2 (Runx2), a well-known bone-specific transcription factor, is also expressed in solid tumors, where expression promotes both bone metastasis and osteolysis. However, the function of Runx2 in MM remains unknown. The current study demonstrated that (1) Runx2 expression in primary human MM cells is significantly greater than in plasma cells from healthy donors and patients with monoclonal gammopathy of undetermined significance; (2) high levels of Runx2 expression in MM cells are associated with a high-risk population of MM patients; and (3) overexpression of Runx2 in MM cells enhanced tumor growth and disease progression in vivo. Additional studies demonstrated that MM cell-derived Runx2 promotes tumor progression through a mechanism involving the upregulation of Akt/b-catenin/Survivin signaling and enhanced expression of multiple metastatic genes/proteins, as well as the induction of a bone-resident cell-like phenotype in MM cells. Thus, Runx2 expression supports the aggressive phenotype of MM and is correlated with poor prognosis. These data implicate Runx2 expression as a major regulator of MM progression in bone and myeloma bone disease. (Blood. 2015;125(23):3598-3608) IntroductionMultiple myeloma (MM) is a largely incurable B-cell malignancy characterized by the clonal expansion of malignant plasma cells in the bone marrow.1-3 A hallmark of MM is the predominant localization in the bone marrow and the propensity for progression from primary bone sites to new bone sites in both local and distant bones. 2,4 Bone disease occurs in ;90% of patients with MM 5 and is the main cause of patient mortality, however, the cellular mechanisms driving MM progression in bone remain largely undefined.Runt-related transcription factor 2 (Runx2), a member of the runtrelated gene family, is a bone-specific transcription factor 6,7 considered to be the master regulator of osteoblastogenesis and bone formation. [6][7][8][9] Accumulating evidence has demonstrated that various solid tumors, such as breast and prostate cancers, also express Runx2 [10][11][12][13][14][15][16][17] and that Runx2 expression is significantly correlated with the development of bone metastasis and subsequent osteolysis. [10][11][12][13][14][15][16][17][18][19] Despite the evidence in solid tumors, the role of Runx2 in MM remains unclear. In this study, the regulatory roles and mechanisms of Runx2 in the promotion of MM growth, survival, and progression in bone were elucidated. Materials and methods Cell lines and cell cultureMouse myeloma 5TGM1 cells were a gift from Dr Claire M. Edwards (University of Oxford, Oxford, United Kingdom). Human myeloma MM.1R cells were purchased from American Type Culture Collection. All...

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“…Factors that are crucial during embryogenesis are often hijacked during cancer progression, and RUNX2 is not an exception. RUNX2 is increasingly recognized in cancer biology for its oncogenic properties and a large number of articles link the deregulation of RUNX2 expression with progression and metastasization of different types of epithelial tumors (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Regulation of RUNX2 may occur at multiple levels and through multiple signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Sancisi¹,

Gandolfi²,

Ambrosetti

et al. 2015

Cancer Research

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Aberrant reactivation of embryonic pathways occurs commonly in cancer. The transcription factor RUNX2 plays a fundamental role during embryogenesis and is aberrantly reactivated during progression and metastasization of different types of human tumors. In this study, we attempted to dissect the molecular mechanisms governing RUNX2 expression and its aberrant reactivation. We identified a new regulatory enhancer element, located within the RUNX2 gene, which is responsible for the activation of the RUNX2 promoter and for the regulation of its expression in cancer cells. Furthermore, we have shown that treatment with the anticancer compounds histone deacetylase inhibitor (HDACi) results in a profound inhibition of RUNX2 expression, which is determined by the disruption of the transcription-activating complex on the identified enhancer. These data envisage a possible targeting strategy to counteract the oncongenic function of RUNX2 in cancer cells and provide evidence that the cytotoxic activity of HDACi in cancer is not only dependent on the reactivation of silenced oncosuppressors but also on the repression of oncogenic factors that are necessary for survival and progression.Cancer Res; 75(9); 1868-82. Ó2015 AACR.

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Ectopic Runx2 Expression in Mammary Epithelial Cells Disrupts Formation of Normal Acini Structure: Implications for Breast Cancer Progression

Cited by 80 publications

References 42 publications

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

Genomic Promoter Occupancy of Runt-related Transcription Factor RUNX2 in Osteosarcoma Cells Identifies Genes Involved in Cell Adhesion and Motility

Myeloma cell–derived Runx2 promotes myeloma progression in bone

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

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