Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells

Pande, Sandhya; Browne, Gillian; Padmanabhan, Srivatsan; Zaidi, Sayyed K.; Lian, Jane B.; Wijnen, André J. van; Stein, Janet L.

doi:10.1002/jcp.24339

Cited by 59 publications

(46 citation statements)

References 38 publications

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“…Zhang et al (13) previously reported that Mfn2 mediates the proliferation of pulmonary artery smooth muscle cells via the PI3K/Akt signaling pathway. Although there have been a number of studies on the PI3K/Akt pathway and breast cancer in recent years (21)(22)(23), none of these studies have demonstrated that the PI3K/Akt signaling pathway is downstream of Mfn2. Our data suggests that Mfn2 decreased Akt activity in the presence of E2, and that Akt is downstream of Mfn2.…”

Section: Mfn2 Suppresses Cell Cycle Progression Via the Pi3k/akt Signmentioning

confidence: 99%

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

Chang

et al. 2015

Oncology Letters

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Abstract. The mitochondrial GTPase mitofusin-2 (Mfn2) gene is a novel gene characterized as a cell proliferation inhibitor. Mfn2 has previously been reported to play a role in regulating cell proliferation, apoptosis and differentiation in a number of cell types. However, there are no studies on the effect of Mfn2 in breast cancer. In this study, we aimed to elucidate the function and mechanism of Mfn2 in breast cancer. A plasmid encoding the complete Mfn2 open reading frame (pEGFP-Mfn2) was used to infect breast cancer cells. The effect of Mfn2 on proliferation was assessed by methyl thiazolyl tetrazolium and bromodeoxyuridine incorporation analyses. Flow cytometry, immunofluorescence and western blot analyses were used to test the effects of Mfn2 on cell cycle distribution and apoptosis. Additionally, the PI3K/Akt signaling pathway was analyzed after pEGFP-Mfn2 was transfected into MCF-7 cells. The results revealed that Mfn2 suppressed the proliferation of MCF-7 cells by regulating more cells at the G0/G1 phase and decreasing proliferating cell nuclear antigen and cyclin A expression. The results also demonstrated that the PI3K/Akt signaling pathway is involved in Mfn2-regulated proliferation and apoptosis. Taken together, this indicates that Mfn2 mediates MCF-7 cell proliferation and apoptosis via the PI3K/Akt signaling pathway. Mfn2 may thus be a significant therapeutic target in the treatment of breast cancer. IntroductionThe mitochondrial GTPase mitofusin-2 (Mfn2) gene, which is also called the hyperplasia suppressor gene, was originally identified in vascular smooth muscle cells from spontaneously hypertensive rats, which exhibited markedly lower expression than Wistar-Kyoto rats (1). Mfn2 localizes to the mitochondrial outer membrane and plays an essential role in mitochondrial fusion, thus regulating mitochondrial morphology and function. Further research has indicated that Mfn2 has a potential apoptotic effect mediated by the mitochondrial apoptotic pathway (1-3). Chen et al (4) demonstrated that Mfn2 notably suppresses cell growth and proliferation in a number of tumor cell lines through the inhibition of the Ras-ERK MAPK signaling pathway. Recently, Mfn2 has become a focal point in tumor research. Several studies have investigated the function of Mfn2 in various malignancies, including hepatocellular, urinary bladder and gastric cancers, and Mfn2 is considered to perform pro-apoptotic and anti-proliferative functions (5-7).Clinical and epidemiological evidence reveals that estrogens participate in the initiation and development of human breast cancer (8,9). Understanding the role of estrogen receptor (ER) α and β in the pathogenesis of breast cancer is essential, since the effects of estrogen are mediated through these two ERs (10). Although the function of ERα has been established and this receptor remains the most significant marker of the response to hormonal therapy in breast cancer, the role of ERβ remains elusive as a result of a number of conflicting studies (11). Our previous study demonstrat...

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Section: Mfn2 Suppresses Cell Cycle Progression Via the Pi3k/akt Signmentioning

confidence: 99%

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

Chang

et al. 2015

Oncology Letters

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“…The peptide, residues 26 -38 phosphorylated at Ser28, was also observed without O-GlcNAc modification. Ser28 is phosphorylated downstream of ERK/MAPK, PI3K/Akt, and PTH/PKA pathways (17,21,58,59), and phosphorylation at this site has been implicated in PTH-induced expression of MMP13 (21) as well as invasive properties of metastatic breast cancer cells (58).…”

Section: Pharmacological Inhibition Of Oga Enhances Runx2 Activity Inmentioning

confidence: 99%

O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells

Nagel

Ball

2014

Molecular & Cellular Proteomics

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Runx2 [also known as: core binding factor ␣ 1 (CBFA1); acute myeloid leukemia transcription factor 3 (AML3); polyoma enhancer-binding protein 2␣ (PEPB2␣)] is a member of the runt-domain gene family of DNA binding proteins (Runx1, Runx2, and Runx3), which control the expression of numerous genes involved in cell growth, proliferation, and determination of cell lineage (1). Aberrant expression and activity of Runx proteins are implicated in leukemia, metastatic breast cancer, and defects in skeletal development and bone remodeling (2-4). Runx2 is expressed during early embryonic development in mesenchymal and cartilage condensations of the developing bone anlagen, and its transcription, activity, and stability are tightly regulated (5-7). Considered the master regulator of osteoblast differentiation, Runx2 also contributes to chondrocyte maturation (8,9) and, through these cell-types, controls intramembranous and endochondral ossification culminating in the formation of the mineralized skeleton (5, 6, 10). A gain-of-function mutation of Runx2, resulting from duplication of exons 3 to 5, is linked to dysplastic long bone formation, enlarged clavicles, and thickening of the cranial vault (11). Conversely, the rare autosomal dominant disorder, cleidocranial dysplasia, has been traced to multiple loss-of-function mutations within the Cbfa1 gene, and is characterized by defective formation or absence of the clavicle, enlarged fontanelles, and dental abnormalities (9, 12, 13). Mice nullizygous for Runx2 develop a cartilaginous skeletal framework that fails to undergo mineralization caused by the absence of osteoblasts, and these mice die at birth because of respiratory failure (5, 10).

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“…Such a phenotype has been suggested for breast cancer cells. 54 Indeed, RNASeq analyses of Runx2 k/in or Runx2 k/d cells revealed that multiple osteogenic genes were significantly increased in Runx2 k/in and decreased in Runx2 k/d MM cells. The osteogenic genes regulated included osteocalcin, OPN, DMP1, as well as osteoclast markers RANK, MMP-9, and CtsK.…”

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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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Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells

Cited by 59 publications

References 38 publications

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells

Myeloma cell–derived Runx2 promotes myeloma progression in bone

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