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      Integrated Molecular Analysis of Tamoxifen-Resistant Invasive Lobular Breast Cancer Cells Identifies MAPK and GRM/mGluR Signaling as Therapeutic Vulnerabilities

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          Abstract

          Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy.

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          Author and article information

          Journal
          7500844
          3382
          Mol Cell Endocrinol
          Mol. Cell. Endocrinol.
          Molecular and cellular endocrinology
          0303-7207
          1872-8057
          4 October 2017
          19 September 2017
          15 August 2018
          15 August 2019
          : 471
          : 105-117
          Affiliations
          [1 ]Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
          [2 ]Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
          [3 ]Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
          [4 ]University of California Los Angeles (UCLA), Los Angeles, CA, USA
          [5 ]Fred Hutchinson Cancer Research Center, Seattle, WA, USA
          [6 ]MTA TTK Lendület Cancer Biomarker Research Group, and 2 nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
          Author notes
          [* ]To whom correspondence should be addressed: 3970 Reservoir Rd NW, E412 Research Bldg., Washington, DC 20057, phone: (202) 687-1260, rebecca.riggins@ 123456georgetown.edu
          Article
          PMC5858970 PMC5858970 5858970 nihpa909796
          10.1016/j.mce.2017.09.024
          5858970
          28935545
          953358e0-1f61-4af9-a728-c0b83a69a832
          History
          Categories
          Article

          Riluzole,mGluR (GRM),ESRRG (ERRgamma),MAPK/ERK (MAPK1),Tamoxifen resistance,Invasive lobular breast cancer (ILC)

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