Brain Metastasis of Breast Cancer: Crossing the Blood-brain Barrier

Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors.

Download Full-text

Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

International Journal of Molecular Sciences ◽

10.3390/ijms21113851 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3851

Author(s):

Golnaz Morad ◽

Cassandra Daisy ◽

Hasan Otu ◽

Towia Libermann ◽

Simon Dillon ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Brain Barrier ◽

Matrix Remodeling ◽

Clinical Challenge ◽

Blood Brain ◽

Dismal Prognosis ◽

Breast Cancer Brain Metastasis

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood–brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

Download Full-text

Breast Cancer Brain Metastasis—Overview of Disease State, Treatment Options and Future Perspectives

Cancers ◽

10.3390/cancers13051078 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1078

Author(s):

Chikashi Watase ◽

Sho Shiino ◽

Tatsunori Shimoi ◽

Emi Noguchi ◽

Tomoya Kaneda ◽

...

Keyword(s):

Breast Cancer ◽

Central Nervous System ◽

Nervous System ◽

Radiation Therapy ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Future Perspectives ◽

Blood Brain ◽

The Central Nervous System

Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood–brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials.

Download Full-text

Brain Metastasis of Breast Cancer: Crossing the Blood-brain Barrier

10.24983/scitemed.jacp.2017.00043 ◽

2017 ◽

Vol 1 (1) ◽

Cited By ~ 2

Author(s):

Jieliang Li

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain

Download Full-text

SNORA71B promotes breast cancer cells across blood–brain barrier by inducing epithelial-mesenchymal transition

Breast Cancer ◽

10.1007/s12282-020-01111-1 ◽

2020 ◽

Vol 27 (6) ◽

pp. 1072-1081

Author(s):

Sijia Duan ◽

Xuliang Luo ◽

Huihui Zeng ◽

Xiang Zhan ◽

Chunlei Yuan

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Cancer Cells ◽

Cancer Patients ◽

Blood Brain Barrier ◽

Epithelial Mesenchymal Transition ◽

Brain Barrier ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Blood Brain

Abstract Background Brain metastasis (BM) is a dreadful complication that significantly impacts the quality of life in breast cancer patients. A key process during brain metastasis is the migration of cancer cells across blood–brain barrier (BBB). However, the role of snoRNAs regulating BBB in BM is still unknown. Methods Here SNORic and GEO databases were used to identify differentially expressed snoRNAs between brain metastatic and non-metastatic breast cancer (BC) tissues. The effects of SNORA71B on the capacities of proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and BBB invasion of BC cells were evaluated by CCK8, transwell, western blot, and BBB model, respectively. Results SNORA71B was highly expressed in high BM BC tissues and cells compared to low BM BC controls. Survival analysis revealed high expression of SNORA71B was significantly associated with poor PPS and OS in breast cancer patients. ROC curve showed that SNORA71B might act as biomarker for breast cancer. Moreover, SNORA71B significantly promoted proliferation, migration, and invasion of BC cells with different BM abilities. Importantly, SNORA71B promoted the EMT process of low BM BC cells. SNORA71B knockdown inhibited the high BM BC cells across BBB, while EMT activator dramatically abrogated this inhibited effect. Conclusions In conclusion, SNORA71B promotes BC cells across the BBB partly via inducing EMT.

Download Full-text

Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1427-1 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 3

Author(s):

Simon Bernatz ◽

Elena I. Ilina ◽

Kavi Devraj ◽

Patrick N. Harter ◽

Klaus Mueller ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Brain Barrier ◽

Patient Cohort ◽

Blood Brain ◽

Metastatic Setting ◽

The Impact

Abstract Background Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. Methods A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. Results Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. Conclusion In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.

Download Full-text

Challenging metastatic breast cancer with the natural defensinPvD1

Nanoscale ◽

10.1039/c7nr05872a ◽

2017 ◽

Vol 9 (43) ◽

pp. 16887-16899 ◽

Cited By ~ 7

Author(s):

Tiago N. Figueira ◽

Filipa D. Oliveira ◽

Inês Almeida ◽

Érica O. Mello ◽

Valdirene M. Gomes ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Brain Metastasis ◽

Tumor Cells ◽

Blood Brain Barrier ◽

Metastatic Breast ◽

Biomechanical Properties ◽

Brain Barrier ◽

Blood Brain ◽

Metastasis Development

PvD1 hampers brain metastasis development by manipulating the biomechanical properties of tumor cells and preventing their adhesion to the blood–brain-barrier.

Download Full-text