Glutamine Metabolism Drives Growth in Advanced Hormone Receptor Positive Breast Cancer

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dc.contributor.authorDemas, Diane M.en
dc.contributor.authorDemo, Susanen
dc.contributor.authorFallah, Yassien
dc.contributor.authorClarke, Roberten
dc.contributor.authorNephew, Kenneth P.en
dc.contributor.authorAlthouse, Sandraen
dc.contributor.authorSandusky, Georgeen
dc.contributor.authorHe, Weien
dc.contributor.authorShajahan-Haq, Ayesha N.en
dc.date.accessioned2019-10-24T19:02:08Zen
dc.date.available2019-10-24T19:02:08Zen
dc.date.issued2019-08-02en
dc.description.abstractDependence on the glutamine pathway is increased in advanced breast cancer cell models and tumors regardless of hormone receptor status or function. While 70% of breast cancers are estrogen receptor positive (ER+) and depend on estrogen signaling for growth, advanced ER+ breast cancers grow independent of estrogen. Cellular changes in amino acids such as glutamine are sensed by the mammalian target of rapamycin (mTOR) complex, mTORC1, which is often deregulated in ER+ advanced breast cancer. Inhibitor of mTOR, such as everolimus, has shown modest clinical activity in ER+ breast cancers when given with an antiestrogen. Here we show that breast cancer cell models that are estrogen independent and antiestrogen resistant are more dependent on glutamine for growth compared with their sensitive parental cell lines. Co-treatment of CB-839, an inhibitor of GLS, an enzyme that converts glutamine to glutamate, and everolimus interrupts the growth of these endocrine resistant xenografts. Using human tumor microarrays, we show that GLS is significantly higher in human breast cancer tumors with increased tumor grade, stage, ER-negative and progesterone receptor (PR) negative status. Moreover, GLS levels were significantly higher in breast tumors from African-American women compared with Caucasian women regardless of ER or PR status. Among patients treated with endocrine therapy, high GLS expression was associated with decreased disease free survival (DFS) from a multivariable model with GLS expression treated as dichotomous. Collectively, these findings suggest a complex biology for glutamine metabolism in driving breast cancer growth. Moreover, targeting GLS and mTOR in advanced breast cancer may be a novel therapeutic approach in advanced ER+ breast cancer.en
dc.description.notesThis work was partly supported by a Sponsored Research grant from Calithera Biosciences and Public Health Service grant R01-CA201092 to AS-H. We thank the Vera Bradley Foundation for Breast Cancer Research (Indiana University) for providing funding support for generating the TMAs. Technical services were provided by the following shared resources at Georgetown University Medical Center: Animal Models, Metabolomics, and Tissue Culture Core Shared Resources that were funded through Public Health Service award 1P30-CA-51008 (Lombardi Comprehensive Cancer Center Support Grant).en
dc.description.sponsorshipVera Bradley Foundation for Breast Cancer Research (Indiana University); Public Health ServiceUnited States Public Health Service [1P30-CA-51008, R01-CA201092]; Calithera Biosciencesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fonc.2019.00686en
dc.identifier.issn2234-943Xen
dc.identifier.other686en
dc.identifier.pmid31428575en
dc.identifier.urihttp://hdl.handle.net/10919/95045en
dc.identifier.volume9en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectbreast canceren
dc.subjectendocrine resistanceen
dc.subjectglutamine metabolismen
dc.subjectmTORen
dc.subjectCB-839en
dc.subjecteverolimusen
dc.titleGlutamine Metabolism Drives Growth in Advanced Hormone Receptor Positive Breast Canceren
dc.title.serialFrontiers in Oncologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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