RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes

Recouvreux, María Sol; Grasso, Esteban; Echeverria, Pablo Christian; Rocha-Viegas, Luciana; Castilla, Lucio H.; Schere-Levy, Carolina; Tocci, Johanna M.; Kordon, Edith C.; Rubinstein, Natalia

doi:10.18632/oncotarget.6771

Cited by 39 publications

(37 citation statements)

References 58 publications

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“…Interestingly, we determined a positive association of RSPO3 with LGR4-6 and RUNX3, which are also overrepresented in the basal subtype. Although a dual activity of RUNX genes in promoting or inhibiting breast cancer development has been established (51), the data shown herein are consistent with our recent report showing that RUNX1 activates the transcription of Rspo3 in mouse mammary tumor cells (33). Therefore, we propose that deregulation of the RUNX family might also lead to RSPO3 overexpression in human breast cancer.…”

Section: Discussionsupporting

confidence: 92%

“…7F), and showed a positive correlation with the runt-related transcription factor (RUNX) family (Supplementary Fig. S5B) that may induce Rspo3 expression in mammary tumor cells (33). Particularly, RSPO3 levels significantly correlated with LGR4-6 and RUNX3 levels, among the members of these two families (Fig.…”

Section: Rspo3 Is Overexpressed In Human Breast Cancer and Is Associamentioning

confidence: 89%

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R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells

et al. 2018

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R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes, including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among patients with breast cancer. Thus, we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers. These findings identify RSPO3 as a potential therapetuic target in basal-like breast cancers. http://cancerres.aacrjournals.org/content/canres/78/16/4497/F1.large.jpg .

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Section: Discussionsupporting

confidence: 92%

Section: Rspo3 Is Overexpressed In Human Breast Cancer and Is Associamentioning

confidence: 89%

R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells

et al. 2018

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“…However, we cannot rule out the possibility that RUNX1 may have other functions in breast cancer, especially in late stage disease. For example, in the MMTV-PyMT mouse model, the level of RUNX1 is positively correlated with tumor progression (35) and regulates genes promoting tumor growth in late stage MDA-MB-231 breast cancer cells (49). However in our study, we found that metastatic MCF10CA1a cells with RUNX1 overexpression formed smaller tumors in mouse mammary fat pad indicating that RUNX1 functions to reduce tumor growth.…”

Section: Discussioncontrasting

confidence: 67%

RUNX1 suppresses breast cancer stemness and tumor growth

Hong

et al. 2018

Preprint

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Recent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved.We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors. Introduction:Breast tumors are heterogeneous, as they are comprised of several types of cells, including transformed cancer cells, supportive cells, tumor-infiltrating cells and cancer stem cells (CSC).The CSC is acknowledged to be a significant component of growing tumors (1) (2). As the name implies, CSC can self-renew and reconstitute the cellular hierarchy within tumors (3) (4). Moreover, these stem-like cells are highly chemo-resistant and metastatic (5) (6).Significantly, signaling pathways (TGF-β, WNT, Hedgehog and Notch) and transcription factors (Snail, Twist and Zeb) regulating stemness properties in CSC are involved in controlling an essential cellular process designated epithelial-mesenchymal transition (EMT) (7,8). The EMT process is linked to chemo-resistance and cancer metastasis (9, 10) (11). One such example is Zeb1, a well-known EMT-activator that is also a key factor for cell plasticity and promotes stemness properties in breast and pancreatic cancers (12) (13). However there remains a compelling requirement to understand regulatory mechanisms that contribute to and sustain the stemness of the CSC population. By identifying regulator(s) that maintain or repress the cancer stem cell phenotype can provide insights for novel therapeutic approaches. Recently, a list of 40 mutation-driver genes for which deregulation contributes directly to breast tumor progression has been identified (14); among these is the transcription factor RUNX1, which has been shown to repress EMT. Here we address for the first time, the function of RUNX1 in regulating breast cancer stem cells.The Runx family, including RUNX1, Runx2 and Runx3, are evolutionarily conserved transcription factors and function as critical lineage determinants of various tissues (15).

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“…Previous studies have demonstrated that the transcription factor RUNX1 regulates apoptosis in acute myeloid leukemia [16], colorectal cancer [17], gastric cancer [18] and breast cancer [19]. However, the role of RUNX1 in NB and how it modulates apoptosis in NB remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Runt-related transcription factor 1 promotes apoptosis and inhibits neuroblastoma progression in vitro and in vivo

Hong

et al. 2020

J Exp Clin Cancer Res

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Background: Runt-related transcription factor 1 (RUNX1) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters and can accelerate apoptosis in various tumors. However, the regulatory mechanisms underlying RUNX1 expression in neuroblastoma (NB), a highly malignant tumor in childhood, remain largely unclear. In this study, we aimed to assess the role of RUNX1 in NB and to reveal the underlying mechanisms that may contribute to finding a potential therapeutics strategy against NB. Methods: Growth, invasion, metastasis and angiogenesis were assessed using Cell Counting Kit-8 (CCK-8) immunocytochemistry, and studies involving soft agar, cell invasion, tube formation and whole animals. The levels of expression were measured using real-time quantitative PCR for RNA, Western blot and immunostaining analyses for proteins. Luciferase reporter and chromatin immunoprecipitation assays indicated that RUNX1 directly binds within the BIRC5, CSF2RB and NFKBIA promoter regions to facilitate transcription. The level of apoptosis was assessed by determining mitochondrial membrane potential and flow cytometry. Results: RUNX1 was highly expressed in ganglioneuroma (GN) and well-differentiated (WD) tissues relative to the poorly differentiated (PD) and undifferentiated (UD) ones. Moreover, RUNX1 effectively reduced cell viability, invasion, metastasis, angiogenesis, and promoted apoptosis in vitro and in vivo. RUNX1 reduced BIRC5 transcription and increased CSF2RB and NFKBIA transcription by directly binding BIRC5, CSF2RB and NFKBIA promoters. In addition, cytotoxic drugs, especially cisplatin, significantly increased RUNX1 expression in NB cells and promoted apoptosis. Conclusions: These data show that RUNX1 is an independent surrogate marker for the progression of NB and it can be used for monitoring NB prognosis during therapy.

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RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes

Cited by 39 publications

References 58 publications

R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells

R-spondin3 Is Associated with Basal-Progenitor Behavior in Normal and Tumor Mammary Cells

RUNX1 suppresses breast cancer stemness and tumor growth

Runt-related transcription factor 1 promotes apoptosis and inhibits neuroblastoma progression in vitro and in vivo

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