title: Astrocyte-induced Reelin expression drives proliferation of Her2+breast cancer metastases.
abstract: Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain's microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2+breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2+metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2+cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2+primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2+cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.
authors.affiliation: Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. rjandial@coh.org.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jandial
authors.affiliation: Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Choy
authors.affiliation: Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Levy
authors.affiliation: Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
authors.forename: Mike Y
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Division of Neurosurgery, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. kansari@coh.org.
authors.forename: Khairul I
authors.initials: KI
authors.lastname: Ansari
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D001374:Azacitidine / Q000494:pharmacology; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D019175:DNA Methylation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018874:Spheroids, Cellular / Q000187:drug effects; D015533:Transcriptional Activation; D064726:Triple Negative Breast Neoplasms / Q000556:secondary; D014407:Tumor Cells, Cultured
chemical_list: D001374:Azacitidine; D015816:Cell Adhesion Molecules, Neuronal; D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C508053:ERBB2 protein, human; C000717127:RELN protein, human
keywords: Astrocytes; Brain metastasis; Breast cancer; ERBB2; Epigenetics; Her2; Neural microenvironment; Reelin; Triple negative breast cancer