Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding

Abstract Background Tamoxifen resistance remains a significant clinical challenge for the therapy of ER-positive breast cancer. It has been reported that the upregulation of transcription factor SOX9 in ER+ recurrent cancer is sufficient for tamoxifen resistance. However, the mechanisms underlying the regulation of SOX9 remain largely unknown. Methods The acetylation level of SOX9 was detected by immunoprecipitation and western blotting. The expressions of HDACs and SIRTs were evaluated by qRT-PCR. Cell growth was measured by performing MTT assay. ALDH-positive breast cancer stem cells were evaluated by flow cytometry. Interaction between HDAC5 and SOX9 was determined by immunoprecipitation assay. Results Deacetylation is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. Furthermore, HDAC5 is the key deacetylase responsible for SOX9 deacetylation and subsequent nuclear translocation. In addition, the transcription factor C-MYC directly promotes the expression of HDAC5 in tamoxifen resistant breast cancer cells. For clinical relevance, high SOX9 and HDAC5 expression are associated with lower survival rates in breast cancer patients treated with tamoxifen. Conclusions This study reveals that HDAC5 regulated by C-MYC is essential for SOX9 deacetylation and nuclear localisation, which is critical for tamoxifen resistance. These results indicate a potential therapy strategy for ER+ breast cancer by targeting C-MYC/HDAC5/SOX9 axis.

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Sirt1 Activator SRT1720 Promotes Tumor Cell Migration And Lung Metastasis In Mouse Models Of Breast Cancer

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2052 ◽

2010 ◽

Author(s):

Kensuke Suzuki ◽

Ryuji Hayashi ◽

Tomomi Ichikawa ◽

Shingo Imanishi ◽

Toru Yamada ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Tumor Cell ◽

Mouse Models ◽

Lung Metastasis ◽

Tumor Cell Migration ◽

Sirt1 Activator

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ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer

Nature Communications ◽

10.1038/s41467-021-25189-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Rokana Taftaf ◽

Xia Liu ◽

Salendra Singh ◽

Yuzhi Jia ◽

Nurmaa K. Dashzeveg ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Lung Metastasis ◽

Lung Metastases ◽

Single Cells ◽

Cluster Formation ◽

Circulating Tumor Cell ◽

Cell Clustering ◽

Lung Colonization ◽

Endothelial Migration

AbstractCirculating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.

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Prognostic impact of transcription factor Fra-1 in ER-positive breast cancer: contribution to a metastatic phenotype through modulation of tumor cell adhesive properties

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-015-1925-2 ◽

2015 ◽

Vol 141 (10) ◽

pp. 1715-1726 ◽

Cited By ~ 8

Author(s):

L. Oliveira-Ferrer ◽

M. Kürschner ◽

V. Labitzky ◽

D. Wicklein ◽

V. Müller ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Tumor Cell ◽

Prognostic Impact ◽

Metastatic Phenotype ◽

Adhesive Properties ◽

Cell Adhesive ◽

Er Positive ◽

Positive Breast Cancer

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Growth factor-dependent regulation of survivin by c-myc in human breast cancer

Journal of Molecular Endocrinology ◽

10.1677/jme.1.02118 ◽

2006 ◽

Vol 37 (3) ◽

pp. 377-390 ◽

Cited By ~ 43

Author(s):

Niamh Cosgrave ◽

Arnold D K Hill ◽

Leonie S Young

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Growth Factors ◽

Growth Factor ◽

Promoter Region ◽

Human Breast Cancer ◽

Luciferase Reporter ◽

Human Breast ◽

Response Element ◽

Factor C

Survivin has emerged as a unique regulator of cell death through its response to growth factors, such as basic fibroblast growth factor (bFGF), which we have previously shown to be mitogen-activated protein kinase (MAPK) dependent. The transcriptional complex myc/max is an oncogene that lies downstream of the MAPK pathway, suggesting a possible role in survivin’s regulation. In this study, we investigated the ability of bFGF to induce signalling of the MAPK effector transcription factor c-myc in human breast cancer. Treatment of SK-BR-3 breast cancer cell line with growth factor induced survivin expression and recruitment of c-myc to its response element in the promoter region of the target gene survivin as demonstrated by electromobility shift analysis and chromatin immunoprecipitation assays. The promoter region of survivin was assessed using bioinformatic techniques and DNA footprinting. Overexpression of c-myc increased survivin protein expression. This effect was eliminated when siRNA against c-myc was transfected into the cells. c-Myc drove transcriptional activity of survivin when transfected into SK-BR-3 cells with a luciferase reporter vector harbouring the c-myc response element specific for survivin. Using confocal fluorescent microscopy, myc was located to the nucleus of breast tumour epithelial cells and was found to be significantly associated with survivin (P < 0.0001). These data provide evidence that growth factors can signal through the transcription factor c-myc in human breast cancer. They also indicate a role for c-myc in the transcriptional regulation of survivin in breast cancer.

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Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1501555112 ◽

2015 ◽

Vol 112 (17) ◽

pp. 5425-5430 ◽

Cited By ~ 97

Author(s):

Liangliang Shen ◽

John M. O’Shea ◽

Mohan R. Kaadige ◽

Stéphanie Cunha ◽

Blake R. Wilde ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Transcription Factor ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Triple Negative ◽

Nutrient Utilization ◽

Gene Signature ◽

Reciprocal Relationship ◽

Factor C

Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc–driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box–containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.

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β-catenin interacts with heat shock protein Hsp27 and heat shock transcription factor 1 and it is a useful prognostic marker in breast cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10593 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10593-10593

Author(s):

F. E. Gago ◽

M. A. Fanelli ◽

M. M. Montt-Guevara ◽

A. M. Diblasi ◽

O. Tello ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Heat Shock ◽

Tumor Cell ◽

Cancer Patients ◽

Prognostic Significance ◽

Heat Shock Transcription Factor ◽

Molecular Pathways ◽

Breast Cancer Patients ◽

Transcription Factor 1

10593 Background: We examined in breast cancer the possible interactions between heat shock proteins (Hsps) and the cadherin- catenin cell adhesion proteins, which have important roles in signaling pathways and tumor cell invasion. The cadherin-catenin proteins, like Hsps, have the capacity to bind other proteins. Moreover, there are common molecular pathways for the Hsp response and for the cadherin- catenin protein system. Methods: β-catenin was immunoprecipitated from breast cancer biopsies and the resulting product was probed with antibodies against Hsp members. LC-ESI-MSMS analysis was performed. Immunohistochemistry was used on paraffin sections. Statistical analyses were performed (Prism computer program): Kaplan-Meier, difference between curves evaluated with the log-rank test for censored survival or event observations, contingency tables analyzed by the Fisher`s exact test and Chi-square. Results: β- catenin interacted with Hsp27 and HSF1 (heat shock transcription factor 1), this is the first demonstration of these specific interactions, β- catenin did not interact with Hsp60, Hsp70, Hsp90, gp96 and CHOP. To confirm this finding, the 27 kDa band was excised and submitted to LC- ESI-MSMS, the band was identified as Hsp27. In addition, β-catenin interacted with P-cadherin and caveolin-1. In the co-localization studies, β- catenin was observed in the same tumor areas and cells that expressed Hsp27. This association was strong when β-catenin was expressed in the cytoplasm, not when β-catenin was expressed at the cell membrane. In addition, β-catenin co-localized with HSF1. Finally, the prognostic significance of cadherin-catenin proteins was examined in breast cancer patients (n=215, follow-up: >10 years). Conclusions: We found that cytoplasmic β-catenin interacted with Hsp27 and HSF1, and that the survival (disease free and overall) was significantly shorter for patients with P-cadherin + and cytoplasmic β-catenin + tumors. The interactions of β-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients. No significant financial relationships to disclose.

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