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?B-crystallin: a novel regulator of breast cancer metastasis to the brain.

ABSTRACT: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone ?B-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of ?B-crystallin in brain metastasis in TNBCs.?B-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. ?B-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing ?B-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models.In a cohort of women with breast cancer brain metastasis, ?B-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of ?B-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing ?B-crystallin inhibited these events. ?B-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an ?3?1 integrin-dependent mechanism. ?B-crystallin overexpression promoted brain metastasis, whereas silencing ?B-crystallin inhibited brain metastasis in orthotopic TNBC models.?B-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.

SUBMITTER: Malin D

PROVIDER: S-EPMC3973485 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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αB-crystallin: a novel regulator of breast cancer metastasis to the brain.

Malin Dmitry D Strekalova Elena E Petrovic Vladimir V Deal Allison M AM Al Ahmad Abraham A Adamo Barbara B Miller C Ryan CR Ugolkov Andrey A Livasy Chad C Fritchie Karen K Hamilton Erika E Blackwell Kimberly K Geradts Joseph J Ewend Matt M Carey Lisa L Shusta Eric V EV Anders Carey K CK Cryns Vincent L VL

Clinical cancer research : an official journal of the American Association for Cancer Research 20131016 1

<h4>Purpose</h4>Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.<h4>Experimental design</h4>αB-crystallin expression in primary breas ...[more]

PMID: 24132917

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Project description:Breast cancer is the most common malignancy among women worldwide, and the main cause of death in patients with breast cancer is metastasis. Metastasis to the central nervous system occurs in 10% to 16% of patients with metastatic breast cancer, and this rate has increased because of recent advancements in systemic chemotherapy. Because of the various treatments available for brain metastasis, accurate diagnosis and evaluation for treatment are important. Magnetic resonance imaging (MRI) is one of the most reliable preoperative examinations not only for diagnosis of metastatic brain tumors but also for estimation of the molecular characteristics of the tumor based on radiographic information such as the number of lesions, solid or ring enhancement, and cyst formation. Surgical resection continues to play an important role in patients with a limited number of brain metastases and a relatively good performance status. A single brain metastasis is a good indication for surgical treatment followed by radiation therapy to obtain longer survival. Surgical removal is also considered for two or more lesions if neurological symptoms are caused by brain lesions of >3 cm with a mass effect or associated hydrocephalus. Although maximal safe resection with minimal morbidity is ideal in the surgical treatment of brain tumors, supramarginal resection can be achieved in select cases. With respect to the resection technique, en bloc resection is generally recommended to avoid leptomeningeal dissemination induced by piecemeal resection. An operating microscope, neuronavigation, and intraoperative neurophysiological monitoring are essential in modern neurosurgical procedures, including tumor resection. More recently, supporting surgical instruments have been introduced. The use of endoscopic surgery has dramatically increased, especially for intraventricular lesions and in transsphenoidal surgery. An exoscope helps neurosurgeons to comfortably operate regardless of patient positioning or anatomy. A tubular retractor can prevent damage to the surrounding brain tissue during surgery and is a useful instrument in combination with both an endoscope and exoscope. Additionally, 5-aminolevulinic acid (5-ALA) is a promising reagent for photodynamic detection of residual tumor tissue. In the near future, novel treatment options such as high-intensity focused ultrasound (HIFU), laser interstitial thermal therapy (LITT), oncolytic virus therapy, and gene therapy will be introduced.

Project description:Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM). LM is rapidly fatal due to poor detection and limited therapeutic options. Therapy of TNBC brain metastasis and LM is challenged by multifocal brain metastasis and diffuse spread of LM, and must balance brain penetration, tumor cytotoxicity, and the avoidance of neurotoxicity. Thus, there is an urgent need for novel therapeutic options in TNBCs CNS metastasis. QBS10072S is a novel chemotherapeutic that leverages TNBC-specific defects in DNA repair and LAT1 (L-amino acid transporter type 1)-dependent transport into the brain. In our study, activity of QBS10072S was investigated in vitro with various cell lines including the human TNBC cell line MDA-MB-231 and its brain-tropic derivative MDA-MB-231-BR3. QBS10072S was preferentially toxic to TNBC cells. The efficacy of QBS10072S against brain metastasis and LM was tested using a model of brain metastasis based on the internal carotid injection of luciferase-expressing tumor cells into NuNu mice. The compound was well tolerated, delayed tumor growth and reduced leptomeningeal dissemination, resulting in significant extension of survival. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, QBS10072S is planned to be investigated in clinical trials as a therapeutic for TNBC LM. SIGNIFICANCE: TNBC brain metastasis often involves dissemination into leptomeninges. Treatment options for TNBC leptomeningeal metastasis are limited and are mostly palliative. Our study demonstrates significant efficacy of the brain-penetrating agent QBS10072S against TNBC brain metastasis and leptomeningeal spread.

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?B-crystallin: a novel regulator of breast cancer metastasis to the brain.

Publications

αB-crystallin: a novel regulator of breast cancer metastasis to the brain.

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