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

Muinelo‐Romay, Laura; Colás, Eva; Barbazán, Jorge; Alonso-Alconada, Lorena; Alonso-Nocelo, Marta; Bouso, Marta; Curiel, Teresa; Cueva, Juan; Anido, Urbano; Forteza, Jerónimo; Gil‐Moreno, Antonio; Reventós, Jaume; López‐López, Rafael; Abal, Miguel

doi:10.1158/1535-7163.mct-10-1019

Cited by 38 publications

(53 citation statements)

References 36 publications

(40 reference statements)

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“…This, together with our finding of increased expression of a TGF-b signaling marker, SERPINE-1 (30), in ER-a-negative tumors suggest that TGF-b is involved in the EMT process in ER-a-negative endometrial carcinomas. A recent study identifying TGF-b as a key factor for invasion in endometrial cancer adds support to this (45). Further studies of functional implications of both TGF-b signaling and ESR1 loss in relation to EMT and PI3K activation in endometrial carcinoma would be highly relevant.…”

Section: Discussionmentioning

confidence: 75%

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

Wik

Ræder

Krakstad

et al. 2013

Clinical Cancer Research

127

119

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Purpose: We hypothesized that estrogen receptor-a (ER-a) status in endometrial carcinomas, associated with poor prognosis, is reflected in transcriptional signatures suggesting targets for new therapy.Experimental Design: Endometrial carcinoma samples in a primary investigation cohort (n ¼ 76) and three independent validation cohorts (n ¼ 155/286/111) were analyzed through integrated molecular profiling. Biomarkers were assessed by immunohistochemistry (IHC), DNA oligonucleotide microarray, quantitative PCR (qPCR), single-nucleotide polymorphism (SNP) array, and Sanger sequencing in the cohorts, annotated for comprehensive histopathologic and clinical data, including follow-up.Results: ER-a immunohistochemical staining was strongly associated with mRNA expression of the receptor gene (ESR1) and patient survival (both P < 0.001). ER-a negativity associated with activation of genes involved in Wnt-, Sonic Hedgehog-, and TGF-b signaling in the investigation cohort, indicating epithelial-mesenchymal transition (EMT). The association between low ER-a and EMT was validated in three independent datasets. Furthermore, phosphoinositide 3-kinase (PI3K) and mTOR inhibitors were among the top-ranked drug signatures negatively correlated with the ER-a-negative tumors. Low ER-a was significantly associated with PIK3CA amplifications but not mutations. Also, low ER-a was correlated to high expression of Stathmin, a marker associated with PTEN loss, and a high PI3K activation signature.Conclusion: Lack of ER-a in endometrial cancer is associated with EMT and reduced survival. We present a rationale for investigating ER-a's potential to predict response to PI3K/mTOR inhibitors in clinical trials and also suggest EMT inhibitors to ER-a-negative endometrial carcinomas.

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Section: Discussionmentioning

confidence: 75%

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

Wik

Ræder

Krakstad

et al. 2013

Clinical Cancer Research

127

119

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“…Elevated levels of ETV5 expression in the Hec1A cell line implied a high impact on cell invasion as demonstrated in an inverted cell invasion assay mimicking migration through a basement membrane and invasion into an extracellular matrix. 24 Cells expressing increased levels of ETV5 were able to migrate and invade deeply into the matrigel (Figure 3a), with more than 10-fold enhanced invasive competences compared with the parental cell as quantified by RT --qPCR (Figure 3b). Similar results were obtained using the Ishikawa endometrial cell line (Supplementary Figure 1D).…”

Section: Etv5 Promotes Emt In Hec1a Cellsmentioning

confidence: 99%

“…24 Briefly, cells were seeded at 5 Â 10 5 cells/ml directly onto the opposite face of the 8 mm size pore membrane transwell (Corning, Lowell, MA, USA) and incubated for 5 h before turning right-side-up. Diluted matrigel growth factor-reduced (BD Bioscience, Franklin Lakes, NJ, USA) was placed over the upper well.…”

Section: Cell Inverted Invasion Assaymentioning

confidence: 99%

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ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

et al. 2012

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Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the female genital tract, with myometrial invasion representing an increase in the rate of recurrences and a decrease in survival. We have previously described ETV5 transcription factor associated with myometrial infiltration in human ECs. In this work, we further investigated ETV5 orchestrating downstream effects to confer the tumor the invasive capabilities needed to disseminate in the early stages of EC dissemination. Molecular profiling evidenced ETV5 having a direct role on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 modulated Zeb1 expression and E-Cadherin repression leading to a complete reorganization of cell --cell and cell --substrate contacts. ETV5-promoted EMT resulted in the acquisition of migratory and invasive capabilities in endometrial cell lines. Furthermore, we identified the lipoma-preferred partner protein as a regulatory partner of ETV5, acting as a sensor for extracellular signals promoting tumor invasion. All together, we propose ETV5-transcriptional regulation of the EMT process through a crosstalk with the tumor surrounding microenvironment, as a principal event initiating EC invasion.

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“…Despite the importance of TGFb in regulating several endometrial cellular activities (4,28), the effect of progesterone on the expression and regulation of TGFb signaling components in human endometrial cancer has not been well characterized. In the present study, we examined the effect of progesterone on the TGFb/SMAD signaling pathway in endometrial cancer cells and showed that progesterone inhibits TGFb-induced R-SMAD expression, nuclear translocation, and subsequently attenuates tumor cell growth and invasiveness by decreasing vimentin and increasing E-cadherin.…”

Section: Introductionmentioning

confidence: 99%

Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

Bokhari

Lee

Raboteau

et al. 2014

Cancer Prevention Research

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Increased expression of TGFb isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFb. The goal of this study was to characterize the effect of progesterone on TGFb signaling pathway components and on TGFb-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFb isoforms at 72 hours after treatment except for TGFb2 in HEC-1B and TGFb3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFb receptors in HEC-1B cells and all but TGFbR1 in Ishikawa cells. Progesterone reduced TGFbR3 expression in RL-95 cells at 72 hours, but TGFbR1 and bR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFb1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFbRI blocked TGFb1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFb signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth. Cancer Prev Res; 7(10); 1045-55. Ó2014 AACR.

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

Cited by 38 publications

References 36 publications

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

Lack of Estrogen Receptor-α Is Associated with Epithelial–Mesenchymal Transition and PI3K Alterations in Endometrial Carcinoma

ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway

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