Stable Spontaneous Fusion of Estrogen Receptor (ER) Positive and ER Negative Breast Cancer Cells Generates an Efficient Model for Breast Cancer Brain Metastasis.

2009 ◽  
Author(s):  
K. De ◽  
A. Bandyopadhyay ◽  
A. Chang ◽  
A. Elkahloun ◽  
J. Cornell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Cancer Brain Metastasis ◽  
Er Positive

scholarly journals BSCI-25. THE ROLE OF THE IFNγ PATHWAY IN BREAST CANCER BRAIN METASTASIS FORMATION

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i5-i5
Author(s):  
Route Pedrosa ◽  
Benjamin Schrijver ◽  
Rute B Marques ◽  
Pieter J M Leenen ◽  
Wim A Dik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells ◽  
Breast Cancer Brain Metastasis

Abstract In previous work, we showed the prominence of the T cell response in the formation of brain metastases of primary ER-negative breast cancers. We also showed that prior co-cultured breast cancer cells with stimulated T lymphocytes bear an overexpression of Guanylate-binding protein 1 (GBP1) and possess an increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to the brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. In the present work, we show that activated CD8+ cytotoxic T lymphocytes, rather than CD4+ lymphocytes, are the main cause of increasing the ability of breast cancer cells to cross the BBB. While synthetic IFNγ does not change the ability of breast cancer cells to cross the BBB, this study shows that the T lymphocyte-secreted IFNγ activates the STAT1-dependent IFNγ pathway in breast cancer cells, enabling them to cross the in vitro BBB. Direct inhibition of soluble IFNγ or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. The results illustrate that IFNγ signaling pathway is one of the crucial pathways in the formation of brain metastasis of ER- breast cancer. The interference with the IFNγ pathway will develop preventive strategies against the formation of brain metastases of breast cancer.

scholarly journals Glucose Transporter 3 Is Essential for the Survival of Breast Cancer Cells in the Brain

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1568 ◽  
Author(s):  
Min-Hsun Kuo ◽  
Wen-Wei Chang ◽  
Bi-Wen Yeh ◽  
Yeh-Shiu Chu ◽  
Yueh-Chun Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Glucose Transporter ◽  
Metastatic Breast ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

Breast cancer brain metastasis commonly occurs in one-fourth of breast cancer patients and is associated with poor prognosis. Abnormal glucose metabolism is found to promote cancer metastasis. Moreover, the tumor microenvironment is crucial and plays an active role in the metabolic adaptations and survival of cancer cells. Glucose transporters are overexpressed in cancer cells to increase glucose uptake. The glucose transporter 3 (GLUT3) is a high-affinity glucose transporter that is highly expressed in mammalian neurons. GLUT3 is also overexpressed in several malignant brain tumors. However, the role of GLUT3 in breast cancer brain metastasis remains unknown. The results of the present study demonstrated that GLUT3 is highly overexpressed in brain metastatic breast cancers and mediates glucose metabolic reprogramming. Furthermore, knockdown of cAMP-response element binding protein (CREB) could directly regulate GLUT3 expression in brain metastatic breast cancer cells. Notably, we verified and provided a novel role of GLUT3 in mediating glucose metabolism and assisting breast cancer cells to survive in the brain to promote brain metastasis.

scholarly journals BSCI-13. TUMOR-SPECIFIC tGLI1 TRANSCRIPTION FACTOR MEDIATES BREAST CANCER BRAIN METASTASIS VIA ACTIVATING METASTASIS-INITIATING CANCER STEM CELLS AND ASTROCYTES IN THE TUMOR MICROENVIRONMENT

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i3-i3
Author(s):  
Sherona Sirkisoon ◽  
Richard Carpenter ◽  
Tadas Rimkus ◽  
Daniel Doheny ◽  
Dongqin Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Ectopic Expression ◽  
Tumor Type ◽  
Primary Tumors ◽  
Breast Cancer Brain Metastasis

Abstract Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive only 6–18 months after diagnosis. Mechanisms for BCBM remain unclear, which contributes to ineffective treatments and dismal prognosis. Truncated glioma-associated oncogene homolog 1 (tGLI1) belongs to the GLI1 family of zinc-finger transcription factors and functions as a tumor-specific gain-of-function mediator of tumor invasion and angiogenesis. Whether tGLI1 plays any role in metastasis of any tumor type remains unknown. Using an experimental metastasis mouse model, via intracardiac implantation, we showed that ectopic expression of tGLI1, but not GLI1, promoted preferential metastasis to brain. Conversely, selective tGLI1 knockdown using tGLI1-specific antisense oligonucleotides led to decreased brain metastasis of intracardially inoculated breast cancer cells. Furthermore, intracranial implantation mouse study revealed tGLI1 enhanced intracranial colonization and growth of breast cancer cells. Immunohistochemical staining of patient samples showed that tGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that tGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. Whether tGLI1 plays any role in radioresistance is unknown; we found radioresistant BCBM cell lines and patient specimens expressed higher levels of tGLI1 than radiosensitive counterparts, and that tGLI1 promotes radioresistance. Since cancer stem cells (CSCs) are highly metastatic and radioresistant, we examined whether tGLI1 promotes BCBM and radioresistance through activating CSCs. Results showed that tGLI1 transcriptionally activates stemness genes CD44, Nanog, Sox2, and OCT4, leading to stem cell activation. Furthermore, we observed that tGLI1-positive CSCs strongly activated and interacted with astrocytes, the most abundant brain tumor microenvironmental cells known to promote tumor growth, in vitro and in vivo. Collectively, our findings establish a novel role of that tGLI1 plays in promoting breast cancer preferential metastasis to brain, radioresistance, and astrocytes in the metastatic niche.

scholarly journals Heat Shock Factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Natalia Vydra ◽  
Patryk Janus ◽  
Paweł Kuś ◽  
Tomasz Stokowy ◽  
Katarzyna Mrowiec ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Heat Shock ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Er Positive ◽  
Positive Breast Cancer

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers, an elevated HSF1 level is associated with metastatic disease.

scholarly journals The mechanisms involved in the resistance of estrogen receptor-positive breast cancer cells to palbociclib are multiple and change over time

2021 ◽  
Author(s):  
Mayu Ono ◽  
Takaaki Oba ◽  
Tomohiro Shibata ◽  
Ken-ichi Ito
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Copy Number ◽  
Breast Cancer Cells ◽  
Copy Number Alterations ◽  
Altered Expression ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Purpose Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used for the treatment of advanced estrogen receptor (ER)-positive breast cancer. To develop a treatment strategy for cancers resistant to CDK4/6 inhibitors, here, we established palbociclib-resistant sublines and analyzed their resistance mechanisms. Methods Palbociclib-resistant sublines were established from T47D and MCF7 cells. Sensitivity to other drugs was assessed via the WST assay. Altered expression/phosphorylation of proteins related to signal transduction and cell cycle regulation was examined using western blotting. Copy number alterations and mutations in the retinoblastoma (RB1) gene were also analyzed. Results Although an increase in CDK6 and decrease in retinoblastoma protein (Rb) expression/phosphorylation were commonly observed in the resistant sublines, changes in other cell cycle-related proteins were heterogeneous. Upon extended exposure to palbociclib, the expression/phosphorylation of these proteins became altered, and the long-term removal of palbociclib did not restore the Rb expression/phosphorylation patterns. Consistently a copy number decrease, as well as RB1 mutations were detected. Moreover, although the resistant sublines exhibited cross-resistance to abemaciclib, their response to dinaciclib was the same as that of wild-type cells. Of note, the cell line exhibiting increased mTOR phosphorylation also showed a higher sensitivity to everolimus. However, the sensitivity to chemotherapeutic agents was unchanged in palbociclib-resistant sublines. Conclusion ER-positive breast cancer cells use multiple molecular mechanisms to survive in the presence of palbociclib, suggesting that targeting activated proteins may be an effective strategy to overcome resistance. Additionally, palbociclib monotherapy induces mutations and copy number alterations in the RB1 gene.

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