High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer

Horimoto, Yoshiya; Sasahara, Noriko; Sasaki, Ritsuko; Hlaing, May Thinzar; Sakaguchi, Asumi; Saeki, Harumi; Arakawa, Atsushi; Himuro, Takanori; Saito, Mitsue

doi:10.1007/s10549-020-05751-x

Cited by 10 publications

(5 citation statements)

References 34 publications

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“…High FOXA1 expression was previously shown to be associated with ERa-positive tumors, smaller tumor size, lower histological grade, and better survival (53). In another study of ERa-positive/HER-2 negative breast cancers high expression of FOXA1 was also linked with small tumor size and independently predicted long disease-free survival (59). This is further supported by a recent study suggesting that high FOXA1 may predict late recurrence in patients with ER-positive breast cancer (59).…”

Section: Discussionmentioning

confidence: 63%

“…In another study of ERa-positive/HER-2 negative breast cancers high expression of FOXA1 was also linked with small tumor size and independently predicted long disease-free survival (59). This is further supported by a recent study suggesting that high FOXA1 may predict late recurrence in patients with ER-positive breast cancer (59). Although the mechanisms of endocrine resistance in breast cancer is complex (36), studies of response to selective estrogen receptor modulators (SERMs) like tamoxifen indicate that negative (corepressors) and positive (coactivators) coregulators of ERa may influence the balance of agonistic versus antagonistic activities of tamoxifen and determine endocrine sensitivity or resistance (36).…”

Section: Discussionmentioning

confidence: 96%

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Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells

Redon

Tang

et al. 2021

Molecular and Cellular Biology

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Susceptibility to breast cancer is significantly increased in individuals with germ line mutations in RECQ1, a gene encoding a DNA helicase essential for genome maintenance. We previously reported that RECQ1 expression predicts clinical outcomes for sporadic breast cancer patients stratified by estrogen receptor (ER) status. Here, we utilized an unbiased integrative genomics approach to delineate a cross talk between RECQ1 and ERα, a known master regulatory transcription factor in breast cancer. We found that expression of ESR1, the gene encoding ERα, is directly activated by RECQ1. More than 35% of RECQ1 binding sites were co-bound by ERα genome-wide. Mechanistically, RECQ1 cooperates with FOXA1, the pioneer transcription factor for ERα, to enhance chromatin accessibility at the ESR1-regulatory regions in a helicase activity-dependent manner. In clinical ERα-positive breast cancers treated with endocrine therapy, high RECQ1 and high FOXA1 co-expressing tumors were associated with better survival. Collectively, these results identify RECQ1 as a novel cofactor for ERα and uncover a previously unknown mechanism by which RECQ1 regulates disease-driving gene expression in ER-positive breast cancer cells.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 96%

Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells

Redon

Tang

et al. 2021

Molecular and Cellular Biology

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“…Previous work by Brinkman et al found that PMDs are associated with CpG island methylation in breast cancer 46 ; PMDs have also been associated with lamina-associated domains (LADs) 47 . Increased expression of FOXA1, one of the few genes found in DNA methylation deserts, has been previously linked to late recurrence 48 . Further research is needed to explore possible mechanisms of these desert regions in NBL.…”

Section: Discussionmentioning

confidence: 99%

A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors

Buckley,

Tew,

Gooden

et al. 2024

npj Precis. Onc.

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Cancer is the second most common cause of death in children aged 1–14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease.

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“…Although FOXA1 is one of the minimal gene features of the ER + luminal breast cancer subgroup, and the functions of FOXA1 and ERα transcriptional programs are tightly coupled, no statistically significant association was found between the level of FOXA1 and overall survival in the ER + breast cancer subgroup ( 42 , 43 ). On the other hand, FOXA1 has also been demonstrated to be a predictor of late recurrence- and distant metastasis-free survival in ER + metastatic breast cancer ( 44 – 46 ). In the current study, we found that FOXA1 expression was correlated with prognostically favorable characteristics, including a low histological grade and an absence of nodal metastasis in breast cancer tissues.…”

Section: Discussionmentioning

confidence: 99%

FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer

Liu,

Yu,

Kong

et al. 2023

Sci. Adv.

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FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β- N -acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr 432 , Ser 441 , and Ser 443 regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2 . Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.

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High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer

Cited by 10 publications

References 34 publications

Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells

Genome-Wide Analysis Unveils DNA Helicase RECQ1 as a Regulator of Estrogen Response Pathway in Breast Cancer Cells

A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors

FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer

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