FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer

Qiu, Meiting; Bao, Wei; Wang, Jingyun; Yang, Tingting; He, Xiaoyun; Liao, Yun; Wan, Xiaoping

doi:10.1186/1471-2407-14-78

Cited by 70 publications

(63 citation statements)

References 47 publications

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“…3E). Furthermore, additional motifs were identified for transcription factors previously described to be involved in endometrial cancer, including androgen receptor (35), progesterone receptor (36), RORB (37), as well as SOX proteins (38). Cumulatively, these data implicate that FOXA1 binds to ERa sites in tamoxifen-associated endometrial cancer that are potentially co-occupied by other transcription factors.…”

Section: Genomic Interactions Of Foxa1 and Era In Endometrial Tumor Smentioning

confidence: 89%

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

et al. 2016

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Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERa) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERa transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERa-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERa was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERa binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERa binding sites proximal to genes involved in classical ERa target genes.Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERa and FOXA1 together with the enhancerenriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERa expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERa in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERa are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. Ó2016 AACR.

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Section: Genomic Interactions Of Foxa1 and Era In Endometrial Tumor Smentioning

confidence: 89%

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

et al. 2016

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“…In our previous study, we found that FOXA1 suppressed the progression of estrogen receptor (ER)-positive EC, which was consistent with other studies (14,18). We also found that FOXA1 promoted cell proliferation via the androgen receptor (AR) and activated Notch pathway in ER-negative, AR-positive EC (19). Thus, FOXA1 is a bifunctional cancer-associated gene, which is oncogenic or tumor suppressive in a context-dependent manner.…”

Section: Discussionmentioning

confidence: 75%

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

et al. 2016

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Abstract. We previously identified FOXA1 as a tumorsuppressor in EC cells. In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC. Using reverse transcription-quantitative PCR (RT-qPCR), we found that FOXA1 expression was significantly downregulated in EC cells compared to that in normal endometrial cells. Functionally, senescence-associated β-galactosidase staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic and Transwell assays showed that in addition to acting as a pioneer factor, FOXA1 was significantly upregulated in senescent EC cells. Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression. All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a , possibly via the AKT pathway. Notably, a selective PI3K inhibitor raised the possibility that FOXA1-induced senescence is associated with the AKT pathway in EC cells. Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression. This may be a newly identified regulatory mechanism of cell senescence in EC.

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“…On the other hand, Sasaki and coworkers reported that AR was not detected in 79% of endometrial carcinomas, although their cases included several unknown histological types (Sasaki et al 2000). Qiu and coworkers recently reported AR-highly expressing cells in 50 of 76 cases (66%) of endometrial carcinoma (Qiu et al 2014). In our previous study, AR immunoreactivity was detected in the nuclei of carcinoma cells and the number of positive cases was 39/44 (89%) (Ito et al 2002).…”

Section: Androgen Receptor Expressionmentioning

confidence: 95%

“…The expression of AR in endometrial carcinoma has been detected in several studies (Horie et al 1992, Sasaki et al 2000, Ito et al 2002, Qiu et al 2014. The number of cases was small (n = 4), but Horie and coworkers reported that all specimens of endometrial carcinoma tissues examined expressed AR (Horie et al 1992).…”

Section: Androgen Receptor Expressionmentioning

confidence: 99%

“…However, such DHT-induced genes have remained largely unknown in endometrial carcinoma. Qiu and coworkers recently demonstrated that the mRNA expression of AR target gene (XBP1, MYC, ZBTB16, and UHRF1) increased after treatment with DHT in the human endometrial carcinoma cell line MFE-296 cells, although the roles of those target genes has still remained virtually unknown (Qiu et al 2014). In addition, the possible roles of androgen-induced genes in endometrial carcinoma have been recently elucidated.…”

Section: Androgen Action From the Viewpoint Of Therapeutic Targetmentioning

confidence: 99%

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In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

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In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

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FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer

Cited by 70 publications

References 47 publications

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

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