Runx2 contributes to the regenerative potential of the mammary epithelium

Ferrari, Nicola; Riggio, Alessandra I.; Mason, Susan; McDonald, Laura; King, Alison; Higgins, Theresa; Rosewell, Ian; Neil, James C.; Smalley, Matthew J.; Sansom, Owen J.; Morris, Joanna S.; Cameron, Ewan R.; Blyth, Karen

doi:10.1038/srep15658

Cited by 30 publications

(27 citation statements)

References 57 publications

(102 reference statements)

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“…Several signaling pathways have been demonstrated to be involved in fibrogenesis, among them are the TGF-b and WNT/b-catenin pathways (5). Here, we observed that both, TGF-b and WNT/b-catenin activation induce RUNX2 expression, which is in line with previous reports that reported RUNX2 to be a WNT/b-catenin target gene in osteoblastic cells or mammary epithelium (18,39). Interplay between RUNX genes and TGF-b signaling can occur at various levels.…”

Section: Discussionsupporting

confidence: 92%

“…In our experiments, loss of RUNX2 in ATII cells led to decreased expression of the proliferation marker Ccnd1 , further suggesting that increased RUNX2 contributes to fibrogenesis by enhancing epithelial proliferation. In line with these findings, depletion of RUNX2 is associated with reduced regenerative potential in mammary epithelium and interferes with mammary organoid formation (39). Murine RUNX2‐negative breast cancers showed reduced levels of CCND1 and Ki‐67 expression compared to RUNX2‐positive breast cancers (43).…”

Section: Discussionmentioning

confidence: 68%

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Cell‐specific expression of runt‐related transcription factor 2 contributes to pulmonary fibrosis

Mümmler¹,

Burgy

Hermann³

et al. 2018

FASEB j.

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Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited therapeutic options and unknown etiology. IPF is characterized by epithelial cell injury, impaired cellular crosstalk between epithelial cells and fibroblasts, and the formation of fibroblast foci with increased extracellular matrix deposition (ECM). We investigated the role of runt-related transcription factor 2 (RUNX2), a master regulator of bone development that has been linked to profibrotic signaling. RUNX2 expression was up-regulated in lung homogenates from patients with IPF and in experimental bleomycin-induced lung fibrosis. The RUNX2 level correlated with disease severity as measured by decreased diffusing capacity and increased levels of the IPF biomarker, matrix metalloproteinase 7. Nuclear RUNX2 was observed in prosurfactant protein C-positive hyperplastic epithelial cells and was rarely found in myofibroblasts. We discovered an up-regulation of RUNX2 in fibrotic alveolar epithelial type II (ATII) cells as well as an increase of RUNX2-negative fibroblasts in experimental and human pulmonary fibrosis. Functionally, small interfering RNA-mediated RUNX2 knockdown decreased profibrotic ATII cell function, such as proliferation and migration, whereas fibroblasts displayed activation markers and increased ECM expression after RUNX2 knockdown. This study reveals that RUNX2 is differentially expressed in ATII cells

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 68%

Cell‐specific expression of runt‐related transcription factor 2 contributes to pulmonary fibrosis

Mümmler¹,

Burgy

Hermann³

et al. 2018

FASEB j.

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“…Activation of the PI3K/Akt pathway could lead to activation of ER-activity without oestrogen stimulation, further contributing to cell growth under tamoxifen treatment. Finally, eIF4E might confer tamoxifen resistance via oestrogen receptor independent pathway due to the activity of mTOR and MNK1 [28], one of the downstream modulators being RUNX2 [33] which is found to be important in breast tumour growth and metastasis [34,35]. Moreover, RUNX2 could regulate the WNT/β-catenin and TCF-β signalling pathways, two pathways essential to tamoxifen resistance [36,37].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

et al. 2020

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Eukaryotic translation initiation factor 4E (eIF4E) selectively promotes translation of mRNAs with atypically long and structured 5′-UTRs and has been implicated in drug resistance. Through genome-wide transcriptome and translatome analysis we revealed eIF4E overexpression could promote cellular activities mediated by ERα and FOXM1 signalling pathways. Whilst eIF4E overexpression could enhance the translation of both ERα and FOXM1, it also led to enhanced transcription of FOXM1. Polysome fractionation experiments confirmed eIF4E could modulate the translation of ERα and FOXM1 mRNA. The enhancement of FOXM1 transcription was contingent upon the presence of ERα, and it was the high levels of FOXM1 that conferred Tamoxifen resistance. Furthermore, tamoxifen resistance was conferred by phosphorylation independent eIF4E overexpression. Immunohistochemistry on 134 estrogen receptor (ER + ) primary breast cancer samples confirmed that high eIF4E expression was significantly associated with increased ERα and FOXM1, and significantly associated with tamoxifen resistance. Our study uncovers a novel mechanism whereby phosphorylation independent eIF4E translational reprogramming in governing the protein synthesis of ERα and FOXM1 contributes to anti-estrogen insensitivity in ER + breast cancer. In eIF4E overexpressing breast cancer, the increased ERα protein expression in turn enhances FOXM1 transcription, which together with its increased translation regulated by eIF4E, contributes to tamoxifen resistance. Coupled with eIF4E translational regulation, our study highlights an important mechanism conferring tamoxifen resistance via both ERα dependent and independent pathways.

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“…Cyp1aCre; Apc fl/fl ; p21 -/mice (hereafter referred to as CAP) were characterised in the Sansom lab as described previously (31). These mice were crossed with Runx1 fl/fl mice (32) (a kind gift from Dr Nancy Speck, Jax:010673, B6;129-Runx1 tm3.1Spe/ J) and/or Runx2 fl/fl mice (33). Tumour mice (equivalent numbers males/females in each cohort) were monitored for signs of tumour development and subsequently checked 3 times a week for signs of endpoint renal failure (blood in urine, hunching, swollen kidneys) (31).…”

Section: Gem Model Of Kidney Cancermentioning

confidence: 99%

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome

et al. 2020

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The recurring association of specific genetic lesions with particular types of cancer is a fascinating, and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown pro-tumorigenic role for the RUNX genes in this disease setting. Analysis of patient tumor biopsies together with loss of function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared to patients with low expression. This was functionally relevant as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability in vitro and in vivo. Transcriptional profiling of RUNX1-CRISPR-deleted cells revealed a gene signature dominated by extracellular matrix remodelling, notably affecting STMN3, SERPINH1, and EPHRIN signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC. Significance: These data reveal a novel unexplored oncogenic role for RUNX genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC. Research.

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Runx2 contributes to the regenerative potential of the mammary epithelium

Cited by 30 publications

References 57 publications

Cell‐specific expression of runt‐related transcription factor 2 contributes to pulmonary fibrosis

Cell‐specific expression of runt‐related transcription factor 2 contributes to pulmonary fibrosis

Phosphorylation independent eIF4E translational reprogramming of selective mRNAs determines tamoxifen resistance in breast cancer

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome

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