Twist1 Promotes Breast Cancer Invasion and Metastasis by Silencing Foxa1 Expression

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Abstract

The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal breast cancer (LBC) with good prognosis, while Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis due to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which plays an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to Foxa1 proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA Polymerase II recruitment. Twist1 also silences Foxa1 promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1's silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.

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Most cited references 36

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Breast cancer molecular subtypes respond differently to preoperative chemotherapy.

Roman Rouzier, Charles Perou, W Symmans … (2005)

Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported "breast intrinsic" gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor-negative subtypes. The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.

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Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.

David Sarrió, Socorro Maria Rodríguez-Pinilla, David Hardisson … (2008)

Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the "basal-like phenotype." Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.

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Concordance among gene-expression-based predictors for breast cancer.

Cheng Fan, Daniel S Oh, Lodewyk F.A. Wessels … (2006)

Gene-expression-profiling studies of primary breast tumors performed by different laboratories have resulted in the identification of a number of distinct prognostic profiles, or gene sets, with little overlap in terms of gene identity. To compare the predictions derived from these gene sets for individual samples, we obtained a single data set of 295 samples and applied five gene-expression-based models: intrinsic subtypes, 70-gene profile, wound response, recurrence score, and the two-gene ratio (for patients who had been treated with tamoxifen). We found that most models had high rates of concordance in their outcome predictions for the individual samples. In particular, almost all tumors identified as having an intrinsic subtype of basal-like, HER2-positive and estrogen-receptor-negative, or luminal B (associated with a poor prognosis) were also classified as having a poor 70-gene profile, activated wound response, and high recurrence score. The 70-gene and recurrence-score models, which are beginning to be used in the clinical setting, showed 77 to 81 percent agreement in outcome classification. Even though different gene sets were used for prognostication in patients with breast cancer, four of the five tested showed significant agreement in the outcome predictions for individual patients and are probably tracking a common set of biologic phenotypes. Copyright 2006 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8711562

Journal ID (pubmed-jr-id): 6325

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date Nihms-submitted: 4 August 2016

Publication date (Electronic): 15 August 2016

Publication date PMC-release: 16 February 2017

Electronic Location Identifier: 10.1038/onc.2016.286

Affiliations

[1 ]Department of Molecular and Cellular Biology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas

[2 ]Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas

[3 ]Institution for Cancer Medicine and College of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China

[4 ]Dan L. Duncan Cancer Center and Department of Medicine-Hematology/Oncology, Baylor College of Medicine, Houston, Texas

Author notes

[* ]Corresponding author: Jianming Xu, PhD, Department of Molecular and Cellular Biology, Baylor College of Medicine. One Baylor Plaza, Houston, TX 77030, USA. jxu@ 123456bcm.edu

Article

Manuscript ID: NIHMS800616

DOI: 10.1038/onc.2016.286

PMC ID: 5311074

PubMed ID: 27524420

SO-VID: ec912cb0-4a5a-44e0-ab0a-c2b68f5ad7d6

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Twist1 Promotes Breast Cancer Invasion and Metastasis by Silencing Foxa1 Expression

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Karger: Oncology

Most cited references 36

Breast cancer molecular subtypes respond differently to preoperative chemotherapy.

Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.

Concordance among gene-expression-based predictors for breast cancer.

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