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

Abstract

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 ...

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

“…Further, a series of studies demonstrated that BC cells that invaded and seeded into the brain tissue are capable to Bmimic^the phenotype of the neuronal cells by acquiring the ability to utilise the specific neurotransmitter which is the γ-aminobutyric acid (GABA) [47,48]. Consequently, the invading breast cancer cells exhibit specific neural characteristics which enable them to penetrate into the brain tissue; thereby, highly activated GABA expression increases their proliferative capacity, particularly within the pre-metastatic niches as the preferable microenvironment.…”

GABA(A) Receptor Pi (GABRP) Stimulates Basal-like Breast Cancer Cell Migration through Activation of Extracellular-regulated Kinase 1/2 (ERK1/2)

“…Most importantly, breast cancer patient brain metastases exhibit a GABAergic phenotype including the up-regulation of GABA(A) receptors, GABA transporters and GAD expression (16). A putative role for GABA(A) in breast cancer is further supported by the observation that propofol, a multifunctional drug with agonist activity for the GABA(A) receptor, induces actin reorganization and migration of breast cancer cells through collagen matrices (17,18).…”

Blood-brain Barrier Remodeling during Brain Metastasis Formation

“…It was suggested that to metastasize to the brain, tumor cells may escape their normative genetic constraints by coinhabiting the neural niche. Indeed, breast tumor cells metastasizing to the brain were found to display a GABAergic phenotype analogous to that of neurons, indicating a metastasis-promoting effect of coinhabitation of the neuronal niche in the brain (76).…”