Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer

• Published in: PloS one Vol. 9; no. 1; p. e81126
• Main Authors: Banda, Malathi, Speyer, Cecilia L, Semma, Sara N, Osuala, Kingsley O, Kounalakis, Nicole, Torres Torres, Keila E, Barnard, Nicola J, Kim, Hyunjin J, Sloane, Bonnie F, Miller, Fred R, Goydos, James S, Gorski, David H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-01-2014; Public Library of Science (PLoS)
• Subjects: Amino acids; Animals; Biology; Breast cancer; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Development and progression; Disease Models, Animal; Disease Progression; Epidermal growth factor; Epidermal growth factors; Epithelium; ErbB-2 protein; Estrogen receptors; Estrogens; FDA approval; Female; Gene Expression; Gene Silencing; Genetic transformation; Glutamate; Glutamatergic transmission; Glutamic acid receptors (metabotropic); Growth factors; Heterografts; Humans; Hyperplasia; In vivo methods and tests; Invasiveness; Kinases; Mathematics; Medical schools; Medicine; Melanoma; Metastasis; Mice; Oncology; Pharmacology; Progesterone; Progesterone receptors; Receptors; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Rodents; Signal Transduction; Signaling; Surgery; Transformation; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Xenografts; Detroit Michigan; United States > US; Michigan; New Brunswick New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0081126

TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy.