FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer

Ray, Partha S.; Wang, Jinhua; Qu, Ying; Sim, Myung Shin; Shamonki, Jaime; Bagaria, Sanjay P.; Ye, Xing; Liu, Bingya; Elashoff, David; Hoon, Dave S.B.; Walter, Michael A.; Martens, John W.M.; Richardson, Andrea L.; Giuliano, Armando E.; Cui, Xiaojiang

doi:10.1158/0008-5472.can-09-4120

Cited by 204 publications

(233 citation statements)

References 25 publications

Supporting

Mentioning

213

Contrasting

Order By: Relevance

“…These findings implicate BRCA1 and GATA3 corepress basal-like breast cancer genes D Tkocz et al FOXC1 as an important mediator of a number of aggressive traits associated with BLBCs and may offer opportunities to develop strategies to overcome drug resistance in this aggressive breast cancer subtype. FOXC1 has been previously identified as a poor prognostic indicator in BLBCs (Ray et al, 2010) and correlated with poor overall survival in BLBC independent of other clinicopathological prognostic factors including lymph node status. The FOXC1 gene has also been reported to be hypomethylated in CD44-positive breast cancer cells and was shown to induce a progenitor-like phenotype in differentiated mammary epithelial cells (Bloushtain-Qimron et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…FOXC1-implications for chemotherapy responses, EMT and breast differentiation FOXC1 expression correlates with worse overall survival in BLBC patients and has been shown to have important roles in epithelial-to-mesenchymal transition (Ray et al, 2010;Taube et al, 2010). Whilst loss of normal BRCA1 function may be a driving event in the emergence of BLBCs, the heterogeneous nature of this poorly defined subtype and the lack of sporadic BRCA1 mutations would suggest that BRCA1 dysfunction is unlikely to be consistent across all BLBCs.…”

Section: Brca1 Interacts With and Requires Gata3 To Repress Foxc1mentioning

confidence: 99%

“…Mutations in the human FOXC1 gene underlie Axenfeld-Rieger syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma. In breast cancer, FOXC1 expression is strongly associated with the basal-like subtype of breast cancer and postulated to be a marker of poor prognosis (Ray et al, 2010;Taube et al, 2010). FOXC1 expression in breast cancers appears to be controlled at the transcriptional level, and methylation of the FOXC1 promoter was shown to be an independent prognostic marker associated with survival (Dejeux et al, 2010) and CD44-positive (basal-like) breast tumors.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Brca1 Interacts With and Requires Gata3 To Repress Foxc1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…23 Recently, Ray et al reported that FOXC1 overexpression is a consistent feature of early invasive breast cancer and basal-like breast cancer. 26 Muggerud et al also reported that FOXC1 knockdown suppressed cell proliferation, migration and invasion in breast cancer cells. 27 Taube et al reported that FOXC1 involvement in an epithelial to mesenchymal transition signature that correlates strongly with poor outcomes in breast cancer.…”

Section: Cancer Cell Biologymentioning

confidence: 96%

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

155

128

View full text Add to dashboard Cite

TXMicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3 0 -untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression-and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.Endometrial cancer is a common cause of gynecological cancer death. The most dominant subtype, endometrioid endometrial cancer (EEC), accounts for >80% of this cancer. Menopause and unopposed estrogenic stimulation are typical risk factors. Patients are generally treated with surgery, radiation, chemotherapy or hormone therapy. Patients with early stage disease have 5-year survival rates over 80%, however, about 15-20% develop metastasis. 1 These patients and those with advanced stage disease or recurrence have poor prognosis due to limitation of effective treatment. 2 Understanding the pathogenesis of this disease may provide insights for the development of novel therapeutic strategies.MicroRNAs (miRNAs) are small noncoding RNA molecules of 19-24 nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes. 4 In human cancers, >50% of the miRNA genes are located in chromosomal fragile sites, minimal regions containing loss of heterozygosity, minimal amplicons or common breakpoint regions. 5 DNA ...

show abstract

“…Most of these tumors are infiltrating ductal tumors with solid growth pattern, aggressive clinical behavior, and high rate of metastasis to the brain and lung. Unlike other BC subtypes, there seems to be no correlation between tumor size and lymph node metastasis in BLBC [1, 11,49]. The most common histological type of BLBC is invasive ductal carcinoma, however BLBC also involves some unique histological types including invasive lobular, medullary, metaplastic, myoepithelial, neuroendocine, apocrine, adenpid cystic, and secretory breast carcinoma [50].…”

Section: Clinicopathological Features Of Blbcmentioning

confidence: 99%

Molecular insights on basal-like breast cancer

Dominguez‐Valentin

Silva

Privat

et al. 2012

Breast Cancer Res Treat

View full text Add to dashboard Cite

Molecular classification of breast cancer (BC) identified diverse subgroups that encompass distinct biological behaviour and clinical implications, in particular in relation to prognosis, spread, and incidence of recurrence. Basal like breast cancers (BLBC) compose up to 15% of BC and are characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification with expression of basal cytokeratins 5/6, 14, 17, epidermal growth factor receptor (EGFR), and/or c-KIT. There is an overlap in definition between triple-negative BC and BLBC due to the triple-negative profile of BLBC. Also, most BRCA1-associated BCs are BLBC, triple negative, and express basal cytokeratins (5/6, 14, 17) and EGFR.There is a link between sporadic BLBC (occurring in women without germline BRCA1 mutations) with dysfunction of the BRCA1 pathway. Despite the molecular and clinical similarities, these subtypes respond differently to neoadjuvant therapy. BLBCs are associated with an aggressive phenotype, high histological grade, poor clinical behavior, and high rates of recurrences and/or metastasis. Their molecular features render these tumors especially refractory to anti-hormonal-based therapies and the overall prognosis of this subset remains poor. In this article the molecular profile, genomic and epigenetic characteristics as well as BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC are presented, with emphasis on the discordant findings in current literature.

show abstract

FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer

Cited by 204 publications

References 25 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

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Molecular insights on basal-like breast cancer

Contact Info

Product

Resources

About