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- Horimoto, Yoshiya, et al.
(författare)
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ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer.
- 2011
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Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 179:3, s. 1148-56
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.
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| 2. |
- Humphries, Matthew P., et al.
(författare)
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A case-matched gender comparison transcriptomic screen identifies eIF4E and eIF5 as potential prognostic markers in male breast cancer
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:10, s. 2575-2583
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.
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