Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells

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• 作者：Jessica L. F. Teh ; Raj Shah ; Stephanie La Cava…
• 关键词：Metabotropic glutamate receptor 1 ; Mammary epithelial cells ; Breast cancer ; Oncogene ; Cell transformation
• 刊名：Breast Cancer Research and Treatment
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：151
• 期：1
• 页码：57-73
• 全文大小：5,935 KB
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• 作者单位：Jessica L. F. Teh (1)
  Raj Shah (1)
  Stephanie La Cava (1)
  Sonia C. Dolfi (2)
  Madhura S. Mehta (2)
  Sameera Kongara (2)
  Sandy Price (2)
  Shridar Ganesan (2)
  Kenneth R. Reuhl (3)
  Kim M. Hirshfield (2)
  Vassiliki Karantza (2) (4)
  Suzie Chen (1) (2)
  
  1. Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
  2. Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA
  3. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
  4. Department of Medicine-Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

Metabotropic glutamate receptor 1 (mGluR1/Grm1) is a member of the G-protein-coupled receptor superfamily, which was once thought to only participate in synaptic transmission and neuronal excitability, but has more recently been implicated in non-neuronal tissue functions. We previously described the oncogenic properties of Grm1 in cultured melanocytes in vitro and in spontaneous melanoma development with 100?% penetrance in vivo. Aberrant mGluR1 expression was detected in 60-0?% of human melanoma cell lines and biopsy samples. As most human cancers are of epithelial origin, we utilized immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the transformative properties of Grm1. We introduced Grm1 into iMMECs and isolated several stable mGluR1-expressing clones. Phenotypic alterations in mammary acinar architecture were assessed using three-dimensional morphogenesis assays. We found that mGluR1-expressing iMMECs exhibited delayed lumen formation in association with decreased central acinar cell death, disrupted cell polarity, and a dramatic increase in the activation of the mitogen-activated protein kinase pathway. Orthotopic implantation of mGluR1-expressing iMMEC clones into mammary fat pads of immunodeficient nude mice resulted in mammary tumor formation in vivo. Persistent mGluR1 expression was required for the maintenance of the tumorigenic phenotypes in vitro and in vivo, as demonstrated by an inducible Grm1-silencing RNA system. Furthermore, mGluR1 was found be expressed in human breast cancer cell lines and breast tumor biopsies. Elevated levels of extracellular glutamate were observed in mGluR1-expressing breast cancer cell lines and concurrent treatment of MCF7 xenografts with glutamate release inhibitor, riluzole, and an AKT inhibitor led to suppression of tumor progression. Our results are likely relevant to human breast cancer, highlighting a putative role of mGluR1 in the pathophysiology of breast cancer and the potential of mGluR1 as a novel therapeutic target.