Loss of Reelin Expression in Breast Cancer Is Epigenetically Controlled and Associated with Poor Prognosis

Stein, Torsten; Cosimo, Emilio; Yu, Xinzi; Smith, Paul; Simon, Ronald; Cottrell, Lorna; Pringle, Marie Anne; Bell, Alison M.; Lattanzio, Laura; Sauter, Guido; Nigro, Cristiana Lo; Crook, T.; Machesky, Laura M.; Gusterson, Barry A.

doi:10.2353/ajpath.2010.100209

Cited by 60 publications

(78 citation statements)

References 38 publications

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“…In susceptible individuals, this might contribute to the onset of SZ as adolescence is a sensitive time period for the remodeling of cortical and limbic circuits (Sisk and Zehr, 2005). Analysis of the RELN promoter in a variety of human cancers shows that RELN is often methylated and that RELN-expressing cancers are less aggressive than RELN-negative cancers (Sato et al, 2006;Stein et al, 2010;Okamura et al, 2011;Dohi et al, 2010). In each of these reports, the data show that increased methylation of the RELN promoter is consistent with transcriptional silencing as measured by RELN mRNA levels.…”

Section: Dna Methylation In Sz and Bp+mentioning

confidence: 99%

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Grayson

Guidotti

2012

Neuropsychopharmacol

239

214

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Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+ ) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+ .

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Section: Dna Methylation In Sz and Bp+mentioning

confidence: 99%

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Grayson

Guidotti

2012

Neuropsychopharmacol

239

214

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“…During development, reelin is produced by a subset of neurons called Cajal-Retzius cells and is integral for their migratory capacity (36). Reelin has also been implicated in the migratory capacity of primary cancer cells (37)(38)(39). To further characterize GABAergic properties, we determined the expression of reelin in BBM cells relative to primary breast cancer.…”

mentioning

confidence: 99%

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

Neman¹,

Termini²,

Wilczynski³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

253

218

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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 brainlike 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 GABA A 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.brain metastasis | tumor microenvironment M etastases are responsible for 90% of all cancer deaths, and patients diagnosed with brain metastases have a dismal 20% probability of 1-y survival (1-3). The brain is increasingly the first site of recurrence after treatment of stage IV advanced breast cancer, even when disease in other sites is in remission. This emerging clinical problem significantly limits the survival gains made from recent advances in systemic therapy for breast cancer (4). Breast cancer metastasizes to the brain in ∼40% of patients who have a tumor that is HER2 + (>30% of tumor cells have complete membrane staining for the tyrosine kinase receptor erbB2) or triple negative (TN) (negative for the estrogen and progesterone receptors and have reduced expression of HER2 + ) (5). Ninety percent of patients with these breast cancer subtypes will die of metastasis to the brain (1). Currently, treatment options beyond radiotherapy and neurological surgery are limited, underscoring the need for research into the biology of these clinically recalcitrant tumors (6).Breast cancer patients typically develop brain metastases months to several years after their initial diagnosis (6). This unique clinical latency occurs despite the early presence of circulating tumor cells, often detectable at the time of primary diagnosis (7-9). These observations suggest that the final step ...

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“…During metastasis, tumor cells have to detach, migrate and re-attach to ECM [107]. Some components of cell adhesion are increased (certain integrins and collagens), while others are downregulated in cancer cells [108][109][110][111][112][113][114]. Differential expression of genes from the ECM-receptor interaction and focal adhesion pathways in the Fischer-344 and Long-Evans strains does not allow us to conclude in which direction these pathways are altered (Table 2) and what advantage or disadvantage it may give to these rats, in terms of breast cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…However, we decided to focus on the expression level of the specific genes and to evaluate their role in breast cancer predisposition. The increased expression of types I and III collagens was detected in human breast cancer [110] whereas loss of reelin was reported to be epigenetically controlled and associated with a poor breast cancer prognosis [112]. Similarly to reelin, laminin alpha 5 was down-regulated in lung cancer and breast carcinoma cells [113,115].…”

Section: Discussionmentioning

confidence: 99%

Gene expression and epigenetic profiles of mammary gland tissue: Insight into the differential predisposition of four rat strains to mammary gland cancer

Luzhna

Kutanzi

Kovalchuk

2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Loss of Reelin Expression in Breast Cancer Is Epigenetically Controlled and Associated with Poor Prognosis

Abstract: Reelin is a secreted, signaling protein associated with neuronal cell positioning and migration. Recently, reelin was found to be epigenetically silenced in gastric and pancreatic cancers in which down-regulation was associated with increased migratory ability and reduced survival.

Cited by 60 publications

References 38 publications

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

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

Gene expression and epigenetic profiles of mammary gland tissue: Insight into the differential predisposition of four rat strains to mammary gland cancer

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