TGF-β signaling is disrupted in endometrioid-type endometrial carcinomas

Piestrzeniewicz‐Ulanska, Dagmara; Bryś, Magdalena; Semczuk, Andrzej; Rechberger, Tomasz; Jakowicki, J; Krajewska, Wanda M.

doi:10.1016/j.ygyno.2004.06.032

Cited by 40 publications

(39 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the uterus, the TGF-b1 pathway has been associated with decidualization, whereas its disruption in both endometrial hyperplasias and carcinomas resulted in the loss of growth inhibition, acting as a key factor in the early steps of endometrial carcinogenesis (32). On the other hand, TGF-b1 receptor type II and other components of the signaling pathway have been associated with myometrial infiltration, local spread and distant metastasis in endometrial carcinomas (33). Our group also linked the TGF-b1 pathway with the increased invasive ability promoted by ETV5 transcription factor during the initial steps of endometrial carcinoma dissemination (22).…”

Section: Discussionmentioning

confidence: 63%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 63%

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

View full text Add to dashboard Cite

show abstract

“…Mutational inactivation of TGFBRII has been identified in pancreatic and biliary cancers (23) as well as in colon cancer (24), and altered expression of SMAD4 is associated with endometrial cancer (25). TFE3 acts synergistically with the Smad3 and Smad4 complex to activate SERPINE1 and Smad7 transcription (26) is inactivated by gene fusions in renal carcinomas (27)(28)(29); BMP7 decreases nuclear accumulation of Smad3 and up-regulation of serine proteinase inhibitor (plasminogen activator inhibitor 1; ref.…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde

Donninger²,

et al. 2006

Cancer Research

View full text Add to dashboard Cite

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-B (TGF-B); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-B signaling were identified that had altered expression >1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-B signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-B signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-B signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-#DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-B. These results suggest that altered expression of these genes is responsible for disrupted TGF-B signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer. (Cancer Res 2006; 66(17): 8404-12)

show abstract

“…On the other hand, increased Smad4 protein expression in 52% hepatocellular carcinomas (HCCs) correlated with higher nuclear grade and increased mitoses [19]. Likewise, in 2 separate studies by Piestrzeniewicz-Ulanska et al [20,21], increased Smad4 protein expression correlated with grade and depth of invasion in tumors of the endometrium. Regarding prostate cancer, although early molecular studies resulted in no point mutations or deletions of the DPC4 gene [22,23], a loss of protein expression associated with tumor progression has been reported more recently [24,25].…”

Section: Discussionmentioning

confidence: 94%

“…Although the loss of DPC4 has been reported in tumors of the pancreas [7], colon [8], and distal common bile duct [9], numerous investigators report infrequent alteration of the DPC4 gene or its protein product in various human malignancies [10], including tumors of the head and neck [11], esophagus and stomach [12], kidney [13], breast [14], lung [15], and endometrium [16], as well as pancreatic endocrine tumors [17] and thyroid follicular carcinoma cell lines [18]. Moreover, increased protein expression has been reported in tumors of the liver [19] and endometrium [20,21].…”

Section: Introductionmentioning

confidence: 99%

Smad4 protein expression correlates with grade, stage, and DNA ploidy in prostatic adenocarcinomas

et al. 2005

View full text Add to dashboard Cite

TGF-β signaling is disrupted in endometrioid-type endometrial carcinomas

Cited by 40 publications

References 35 publications

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

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

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Smad4 protein expression correlates with grade, stage, and DNA ploidy in prostatic adenocarcinomas

Contact Info

Product

Resources

About