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

Abstract

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.

• Authors: Malathi Banda, Cecilia L Speyer, Sara N Semma, Kingsley O Osuala, Nicole Kounalakis, Keila E Torres Torres, Nicola J Barnard, Hyunjin J Kim, Bonnie F Sloane, Fred R Miller, James S Goydos, David H Gorski
• Journal: PloS one (PLoS One) Vol. 9 Issue 1 Pg. e81126 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24404125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor type 1

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Disease Models, Animal
• Disease Progression
• Female
• Gene Expression
• Gene Silencing
• Heterografts
• Humans
• Mice
• Receptors, Metabotropic Glutamate (genetics, metabolism)
• Signal Transduction
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)