Effect of heterogeneity of HER2 expression on brain metastases of breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 635-635
Author(s):  
Mari Hosonaga ◽  
Yoshimi Arima ◽  
Eiji Sugihara ◽  
Norio Kohno ◽  
Hideyuki Saya
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Her2 Expression ◽  
Flow Cytometry Analysis ◽  
Her2 Positive ◽  
The Brain

635 Background: HER2-overexpressing or triple-negative [ER(-)/PR(-)/HER2(-)] breast cancers are associated with increased risk of brain metastases. The mechanisms leading to metastasis in each subtype are not well known. Methods: We introduced the wild-type HER2 gene into MDA-MB-231-luc-D3H2LN (231-Luc) cells, which are triple-negative breast cancer cells, and established HER2-expressing (63.2%) cells as 231-Luc-HER2 cells. We investigated the tumor formation following orthotopic inoculation and brain metastasis following intracardiac injection into nude mice. Metastasis was detected by bioluminescence imaging and confirmed in H&E staining and immunohistochemistry of vimentin and HER2 expressions. Flow cytometry analysis was used to detect the proportion of CD44+/CD24- cells, a maker for stem-like breast cancer cells. Results: 231-Luc-HER2 cells formed larger tumors in orthotopic xenograft models compared to 231-Luc cells, however, no significant difference was observed in proliferation in vitro. Neither 231-Luc-HER2 nor 231-Luc metastasized in the brain from the breast after orthotopic inoculation. After intracardiac injections of the 231-Luc-HER2 cells, brain metastasis developed (7/13 mice, 53.8%). Immunohistochemical analysis revealed that most metastasized cells expressed HER2, although we had injected a mixture of HER2-positive and HER2-negative cancer cells. Interestingly, administering Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, effectively prevented HER2-positive cells to colonize the brain. However, the HER2-negative 231-Luc-HER2 cells developed into brain metastases. In fact, the 231-Luc cells, which are HER2-negative, also metastasized in the brain (10/16 mice, 62.5%). Flow cytometry analysis of the 231-Luc-HER2 cells showed that HER2-positive cells decreased the population of CD44+/CD24- (HER2+/CD44+/CD24-: 86.8% and HER2-/CD44+/CD24-: 96.3%). Conclusions: The mechanism of brain metastases of HER2-positive breast cancer cells is different from that of HER2-negative breast cancer cells. It is therefore important to consider an additional therapeutic approach when dealing with HER2-negative cells in tumors having the heterogeneity of HER2 expression.

scholarly journals Molecular and cellular mechanisms underlying brain metastasis of breast cancer

2020 ◽  
Vol 39 (3) ◽  
pp. 711-720 ◽  
Author(s):  
Mari Hosonaga ◽  
Hideyuki Saya ◽  
Yoshimi Arima
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Breast Cancer Patients ◽  
Cellular Mechanisms ◽  
Her2 Positive ◽  
Cells Of The Microenvironment ◽  
The Brain

Abstract Metastasis of cancer cells to the brain occurs frequently in patients with certain subtypes of breast cancer. In particular, patients with HER2-positive or triple-negative breast cancer are at high risk for the development of brain metastases. Despite recent advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Such interactions result in the activation of various signaling pathways related to metastasis in both cancer cells and cells of the microenvironment including astrocytes and microglia. In this review, we focus on such interactions and on their role both in the metastatic process and as potential targets for therapeutic intervention.

scholarly journals TMIC-10. THE ROLE OF THE BRAIN MICROENVIRONMENT IN THE MIGRATION OF BREAST CANCER CELLS IN BRAIN METASTASES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi249-vi249
Author(s):  
Cymon Kersch ◽  
Leslie Muldoon ◽  
DreeAnna Morris ◽  
Edward Neuwelt
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Αvβ3 Integrin ◽  
Human Breast ◽  
And Migration ◽  
Breast Cancer Brain Metastases ◽  
The Brain

Abstract BACKGROUND Breast cancer brain metastases have poor prognosis and few treatment options. When breast cancer cells invade the brain they interact with the vasculature and resident brain cells including microglia and astrocytes. We hypothesize that brain cells produce factors that enhance the growth and invasion of breast cancer cells in the brain. METHODS Human breast cancer cell lines (MDA-MB231BR-HER2 and HCC1954) were inoculated intracranially in athymic rats as xenograft models of brain metastasis. Brains were analyzed for pro-tumorigenic factor expression in the tumor microenvironment using fluorescent immunohistochemistry. In vitro assays assessed factors involved in breast cancer cell proliferation, morphology, and migration. RESULTS The tumor xenografts showed infiltration intothe perivascular space. Galectin-3 (Gal3), heparin-binding epidermal growth factor (HB-EGF), and Neuregulin (NRG1), factors known to interact with receptors expressed by breast cancer cells, co-localized with reactive microglia (Gal3) and astrocytes (HB-EGF and NRG1) in and around xenografts. In vitro, these factors individually increased HCC1954 cell proliferation and/or migration. In transwell co-culture assays, BV2 microglial cells increased the migration of HCC1954 cells >25 fold, which was prevented by cilengitide, an inhibitor of αvβ3-integrin cell adhesion protein. ELISA analysis demonstrated that BV2 microglia secrete Gal3 in the presence of HCC1954 cells. Gal3 is known to bind and induce clustering of αvβ3-integrin which is expressed on metastatic breast cancer cells. Immunohistochemistry of clinical specimens revealed that Gal3 is expressed in/around human breast cancer brain metastases. CONCLUSIONS These data suggest that factors produced in the tumor microenvironment promote the growth and migration of breast cancer cells in the brain. Gal3, produced and secreted by activated microglia in vitro and expressed in and around brain metastases, increases the invasive capability of breast cancer cells. The interactions of neoplastic cells with the brain environment may provide a target to improve therapy of brain metastases.

scholarly journals Expression of CD 24 is associated with HER2 expression and supports HER2‐Akt signaling in HER2‐positive breast cancer cells

2014 ◽  
Vol 105 (7) ◽  
pp. 779-787 ◽  
Author(s):  
Mari Hosonaga ◽  
Yoshimi Arima ◽  
Eiji Sugihara ◽  
Norio Kohno ◽  
Hideyuki Saya
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals BSCI-02. tGLI1 IS A NOVEL, ACTIONABLE TARGET FOR THE TREATMENT OF BREAST CANCER BRAIN METASTASES

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i1-i1 ◽  
Author(s):  
Daniel Doheny ◽  
Sherona Sirkisoon ◽  
Tadas Rimkus ◽  
Dongqin Zhu ◽  
Noah Aguayo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Unmet Need ◽  
Current Standard ◽  
Recurrent Gliomas ◽  
Breast Cancer Brain Metastases ◽  
The Brain ◽  
Positive Breast Cancer

Abstract Despite improvements in early detection and intervention, breast cancer remains the second leading cause of cancer-related death in women and the second most common cancer to metastasize to the brain. Current standard of care options for breast cancer brain metastases (BCBM) include stereotactic radiosurgery, whole-brain radiotherapy, and surgical resection. Local and distant recurrences are common leading to significant morbidity; effective FDA-approved drugs for these patients remain a significant unmet need. Our laboratory discovered an alternative splice variant of glioma-associated oncogene homolog 1 (GLI1), termed truncated GLI1 (tGLI1) that is a tumor-specific gain-of-function transcription factor preferentially expressed in most BCBM samples and recurrent gliomas. Recent results established that tGLI1 promotes breast cancer stem cells (BrCSCs) and is associated with preferential metastasis to the brain and radioresistance, justifying tGLI1 as an ideal therapeutic target for BCBM patients. To identify tGLI1-targeting agents, we screened 1,520 compounds across three commercial drug libraries and found ketoconazole, an FDA-approved azole antifungal and component of previously studied anti-neoplastic regimens, selectively killed tGLI1-expressing breast cancer cells with heightened efficacy against the CSC subpopulation in vitro. tGLI1 knockdown abolished the ability of ketoconazole to target BrCSCs, indicating that ketoconazole effect is dependent on tGLI1. Intracardiac mouse studies showed ketoconazole selectively inhibited circulating tGLI1-positive breast cancer cells from developing into brain metastases and suppressed the progression of existing brain metastases. Mass spectrometry demonstrated ketoconazole effectively penetrated the blood-brain barrier (BBB) and blood-tumor barrier (BTB). Mechanistic studies suggest that ketoconazole-dependent cell kill is, in part, mediated through disruption of the tGLI1-STAT3 interaction. Collectively, our preclinical results demonstrate that ketoconazole is an effective inhibitor of BrCSCs and brain metastasis of tGLI1-positive breast cancer. Based on these promising preclinical data, we opened a window-of-opportunity study in patients with BCBM and recurrent gliomas to determine if ketoconazole treatment alters tGLI1 signaling in humans (NCT03796273).

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