An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

Doll, Andreas; González, Marta; Abal, Miguel; Llauradó, Marta; Rigau, Marina; Colás, Eva; Monge, Marta; Xercavins, Jordi; Capellà, Gabriel; Díaz, Belén Muñoz; Gil‐Moreno, Antonio; Alameda, Francesc; Reventós, Jaume

doi:10.1002/ijc.24330

Cited by 44 publications

(47 citation statements)

References 36 publications

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“…The link of bulge cell proliferation with tumorigenesis has been a recurring theme in the field, and Runx1 is a known cancer gene in blood (8,39). Runx1 mutations have been associated with acute myeloid leukemia (8), and recently Runx1 was found to be expressed and play a role in endometrial carcinoma in humans (16). Here we have implicated Runx1 in the repression of Cdkn1a (p21), known for its role in stem cell proliferation (see above), for tumor suppression downstream of p53 (31), and in the skin for blocking tumorigenesis in response to DMBA/TPA treatment (58).…”

Section: Discussionmentioning

confidence: 99%

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Hoi

Lee

et al. 2010

Molecular and Cellular Biology

107

135

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Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G 0 /G1 and G 1 /S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Hoi

Lee

et al. 2010

Molecular and Cellular Biology

107

135

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“…Despite the characterization of molecular events associated with the development of type I and type II endometrial carcinoma such as alterations in PTEN, b-catenin, KRAS, p53, or HER-2/neu, the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial carcinoma is almost unknown (12,22,23). Thus, an important clinical impact would be associated with discovering genes or canonical pathways associated with advanced endometrial carcinomas, unmasking the principal common mechanisms of tumor aggressiveness, providing novel markers and developing rational therapies.…”

Section: Discussionmentioning

confidence: 99%

“…This cell line has been described as TGF-b1 sensitive and its metastatic ability partially depends on the correct activation of this route (20). Moreover, our group showed that when injected in mice either subcutaneously or orthotopically, HEC-1A cells generate highly undifferentiated and aggressive tumors representative of high-risk endometrial carcinoma (12). Cells treated with TGF-b1 (2.5 ng/mL) for 24 hours acquired a mesenchymal phenotype characterized by the loss of cell-cell contacts and the promotion of migratory structures as lamellipodia ( Fig.…”

Section: Tgf-b1 Promotes Emt In Endometrial Cancer Cellsmentioning

confidence: 95%

“…Despite the great effort made to establish the pathogenesis of endometrial carcinoma, the key molecular events responsible for tumor invasion and dissemination are still not clearly delineated (12). Gaining insight into the molecular alterations involved in endometrial carcinoma progression and invasion may provide us with opportunities for developing new therapeutic approaches to inhibit tumor spread and to improve the outcome in high-risk endometrial carcinoma patients.…”

Section: Introductionmentioning

confidence: 99%

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High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Muinelo‐Romay

Colás

Barbazán

et al. 2011

Molecular Cancer Therapeutics

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Endometrial cancer is among the three most common cancers in females in industrialized countries. In the majority of cases, the tumor is confined to the uterus at the time of diagnosis and presents a good prognosis. However, after primary surgery, 15% to 20% of these tumors recur and have limited response to systemic therapy. We carried out gene expression profiling of high-risk recurrence endometrial cancers to identify new therapeutic approaches targeting the molecular pathways involved in the acquisition of an aggressive tumor phenotype. A microarray gene-expression analysis on a total of 51 human endometrial carcinomas revealed 77 genes specifically altered in high-risk recurrence tumors (P < 0.001). The bioinformatics analysis of gene-gene interactions and molecular relationships among these genes pointed to a prominent role for TGFb1 signaling in the acquisition of an aggressive phenotype. We further showed that TGF-b1 has a principal role at the initiation of endometrial carcinoma invasion through the promotion of the epithelial to mesenchymal transition that leads to the acquisition of an invasive phenotype in HEC-1A and RL95-2 cells. Impairment of this initial step with SB-431542, a specific TGF-b1 inhibitor, precluded further persistent endometrial carcinoma invasion. In conclusion, we showed that the characterization of the molecular changes associated with the acquisition of an aggressive phenotype represents a realistic strategy for the rational identification and characterization of new potential therapeutic targets in an effort to improve the clinical management and the outcome of high-risk endometrial cancer patients. Mol Cancer Ther; 10(8); 1357-66. '2011 AACR.

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“…These two markers have been found to be deregulated in different types of tumors, including endometrioid, prostate, breast and oral squamous carcinoma together with acute lymphoblastic leukemia (8,9,11,12,14,(18)(19)(20)(21)(22)(23)(24)(25). The present study was designed to address the hypothesis of cohesin deregulation in endometrial cancer.…”

Section: Introductionmentioning

confidence: 98%

Deregulation of RAD21 and RUNX1 expression in endometrial cancer

et al. 2012

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Abstract. Cohesins and cohesin-regulated genes are deregulated in numerous types of human cancer. However, data concerning their status and role in endometrial cancer are scarce. This study aimed to determine the clinical significance of double-strand-break repair protein rad21 homolog (RAD21) and runt-related transcription factor 1 (RUNX1) gene dosage and mRNA expression in endometrial cancer. RAD21 is a component of the cohesin complex, crucial for chromosome segregation and DNA repair. RUNX1 is the transcription factor implicated in RAD21 regulation. The study group included 144 endometrial cancer patients. RAD21 and RUNX1 expression profiles were measured by reverse-transcription quantitative PCR. RAD21 gene dosage was determined by quantitative PCR. RAD21 gene dosage was associated with RAD21 mRNA expression (ρ=0.22; p=0.009). Furthermore, RAD21 expression strongly correlated with RUNX1 expression (ρ=0.43; p<0.0000001). Increased RAD21 gene dosage correlated with more advanced tumor stage (p=0.021), higher grade (p= 0.021), cervical involvement (p= 0.01) and the absence of obesity (p=0.025), while RAD21 mRNA expression correlatd with cervical involvement (p=0.027). The mRNA expression of RAD21 and RUNX1 was found to be deregulated and co-dependent in endometrial cancer. RAD21 gene dosage is associated with unfavorable tumor characteristics. However, elucidating the role of these molecular markers in endometrial oncogenesis requires further investigation, including functional studies and survival analysis.

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An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

Cited by 44 publications

References 36 publications

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Deregulation of RAD21 and RUNX1 expression in endometrial cancer

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