Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

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Abstract

<p class="first" id="Par1">The breast cancer (BC) diagnosis currently experiences the epidemic evolution with more than half of million deaths each year. Despite screening programmes applied and treatments available, breast cancer patients frequently develop distant metastases. The brain is one of the predominant sites of the metastatic spread recorded for more than 20% of BC patients, in contrast to the general population, where brain tumours are rarely diagnosed. Although highly clinically relevant, the brain tumour mystery in the cohort of breast cancer patients has not been yet adequately explained. This review summarises currently available information on the risk factors predicting brain metastases in BC patients to motivate the relevant scientific areas to explore the data/facts available and elucidate disease-specific mechanisms that are of a great clinical utility. </p>

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Genes that mediate breast cancer metastasis to the brain.

Paula Bos, Xiang Zhang, Cristina Nadal … (2009)

The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

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Diversity of Breast Carcinoma: Histological Subtypes and Clinical Relevance

Jaafar Makki (2015)

Mammary carcinoma is the most common malignant tumor in women, and it is the leading cause of mortality, with an incidence of >1,000,000 cases occurring worldwide annually. It is one of the most common human neoplasms, accounting for approximately one-quarter of all cancers in females worldwide and 27% of cancers in developed countries with a Western lifestyle. They exhibit a wide scope of morphological features, different immunohistochemical profiles, and unique histopathological subtypes that have specific clinical course and outcome. Breast cancers can be classified into distinct subgroups based on similarities in the gene expression profiles and molecular classification.

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Human breast cancer metastases to the brain display GABAergic properties in the neural niche.

Rahul Jandial, Nagarajan Vaidehi, Amanda C Hambrecht … (2014)

Dispersion of tumors throughout the body is a neoplastic process responsible for the vast majority of deaths from cancer. Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. The physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by circulating breast cancer cells. Bidirectional interplay of breast cancer cells and native brain cells in metastasis is poorly understood and rarely studied. We had the rare opportunity to investigate uncommonly available specimens of matched fresh breast-to-brain metastases tissue and derived cells from patients undergoing neurosurgical resection. We hypothesized that, to metastasize, breast cancers may escape their normative genetic constraints by accommodating and coinhabiting the neural niche. This acquisition or expression of brain-like properties by breast cancer cells could be a malignant adaptation required for brain colonization. Indeed, we found breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metastases to the brain. Proliferative advantage was conferred by the ability of breast-to-brain metastases to take up and catabolize GABA into succinate with the resultant formation of NADH as a biosynthetic source through the GABA shunt. The results suggest that breast cancers exhibit neural characteristics when occupying the brain microenvironment and co-opt GABA as an oncometabolite.