Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours

Albergaria, André; Paredes, Joana; Sousa, Bárbara; Milanezi, Fernanda; Carneiro, Victor Alves; Bastos, Joana; Costa, Sandra; Vieira, Dioracy Fonterrada; Lopes, Nair; Lam, Eric W.‐F.; Lunet, Nuno; Schmitt, Fernando

doi:10.1186/bcr2327

Cited by 144 publications

(168 citation statements)

References 38 publications

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“…GATA3 has also been reported to be coexpressed with another good prognosis indicator, FOXA1, in luminal A breast cancers and the expression of both proteins are known to predict for good prognosis (Ademuyiwa et al, 2010). There is also evidence that FOXA1 may also predict for better clinical outcome in ERa-negative breast tumours (Albergaria et al, 2009). GATA3 is also known to be required for specification and maintenance of the luminal phenotype in breast tissue (Kouros-Mehr et al, 2006.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

et al. 2011

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In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.

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Section: Discussionmentioning

confidence: 99%

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

et al. 2011

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“…4a). GATA3 is an important transcriptional regulator in both normal mammary gland development and breast cancer [39][40][41] , and low expression levels of GATA3 are associated with a poor prognosis 42 . Three genes, PTCH1, PPARA and NFIB, exhibit epistatic interactions with GATA3 and also display negatively correlated expression levels with GATA3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Widespread genetic epistasis among cancer genes

Wang

McNerney

et al. 2014

Nat Commun

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Quantitative genetic epistasis has been hypothesized to be an important factor in the development and progression of complex diseases. Cancers in particular are driven by the accumulation of mutations that may act epistatically during the course of the disease. However, as cancer mutations are uncovered at an unprecedented rate, determining which combinations of genetic alterations interact to produce cancer phenotypes remains a challenge. Here we show that by using combinatorial RNAi screening in cell culture, dense and often previously undetermined interactions among cancer genes were revealed by assessing gene pairs that are frequently co-altered in primary breast cancers. These interacting gene pairs are significantly associated with survival time when co-altered in patients, indicating that genetic interaction mapping may be leveraged to improve risk assessment. As many of these interacting gene pairs involve known drug targets, personalized treatment regimens may be improved by overlaying genetic interactions with mutational profiling.

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“…[10,11] Within the luminal, a subtype of IC, it has been shown that FOXA1 [10,11] and GATA-3 [22,24] can sub-classify patients into a low and high-risk groups based on their strong expression. FOXA1 via its actions on the p27 promoter, [16,17] is thought to maintain IC in a less proliferative state, with a decreased metastatic potential, [10][11][12][13] while GATA-3 is important in the maintenance of tumor differentiation and suppression of metastatic potential. [21] Therefore, it is not surprising that these transcription factors are highly expressed in DCIS as well, which by defi nition is an in situ (noninvasive) carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…[21] GATA-3 genes are involved with induction of FOXA1 expression, with increased activity in ER(+) carcinoma; therefore, the highest expression of FOXA1 in IC should be seen in association with both GATA-3 and ERα expression, [27] which has been seen in IC. [12] However, this relationship has not yet been categorized in DCIS. The specifi c aim of this study is to analyze the expression for the fi rst time in DCIS of novel biological transcription markers FOXA1, GATA-3, along with established markers MIB-1 (Ki-67) and HER2-neu in ER(+) and ER(-) groups of DCIS.…”

Section: Original Articlementioning

confidence: 99%

“…Their use as prognostic clinical biomarkers has recently been studied in IC but not in DCIS . [10][11][12][13] FOXA1, originally called the hepatocyte nuclear factor 3α, is a ubiquitous transcription factor expressed in liver, breast, prostate, lung, colon, and pancreas that has both activator and repressor activity. As an activator, FOXA1 has the unique ability to bind to its target sites via altering chromatin structure facilitating ERα binding and thus promoting gene expression .…”

Section: Original Articlementioning

confidence: 99%

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Prognostic significance of transcription factors FOXA1 and GATA-3 in ductal carcinoma in situ in terms of recurrence and estrogen receptor status

Chivukula¹,

Picarsic²,

Bulusu³

et al. 2015

J Cancer Metastasis Treat

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Aim:The aim was to analyze the expression of novel biological transcription markers, forkhead-box A1 (FOXA1), GATA binding protein 3 (GATA-3), and established markers such as Ki-67 (MIB-1) and human epidermal growth factor receptor 2 (HER2) in estrogen receptor (ER(+)) and ER(-) ductal carcinoma in situ (DCIS) patients with/without recurrence. Methods: Two hundred and ninety-one cases of DCIS were retrieved from our pathology database, with complete data available for 219 cases. The follow-up period is from 1988 to 2009. Recurrence is defi ned in terms of DCIS or invasive carcinoma (IC). No recurrence was seen in 88% (196/219) of cases; 12% (26/219) had a recurrence (IC: 13, DCIS: 13). We are reporting the results of biological marker expression in terms of recurrence and ER status. Results: Our study demonstrates strong expression of GATA-3 in the ER(+) DCIS in recurrence and nonrecurrence groups similar to previously described in IC. A reduced expression of GATA-3 was observed in ER(-) recurrence and nonrecurrence groups. A strong HER2 protein expression, as well as high proliferation index, was seen in recurrence group (DCIS and IC). FOXA1 expression is reduced across the groups though not statistically signifi cant. Conclusion: This is the fi rst study to analyze novel transcription markers FOXA1 and GATA-3 in DCIS. Further work needs to be done on a larger cohort of DCIS cases with recurrence to better understand, which variables are best able to predict recurrence and guide therapy decision strategies. Maintenance of FOXA1 and GATA-3 expression in ER(-) DCIS may offer new promising targets for therapy in future.

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Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours

Cited by 144 publications

References 38 publications

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

Widespread genetic epistasis among cancer genes

Prognostic significance of transcription factors FOXA1 and GATA-3 in ductal carcinoma in situ in terms of recurrence and estrogen receptor status

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