The small G-protein RalA promotes progression and metastasis of triple-negative breast cancer.
Background: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an...
| Publicado en: | Breast Cancer Research Vol. 23; no. 1; pp. 1 - 18 |
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| Autores principales: | , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
6/12/2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=150892847&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 150892847 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 6/12/2021 vid: 23 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 150892847 150892847 NLM34118960 150892847 10.1186/s13058-021-01438-3 NLM34118960 150892847 ppf: 1 ppct: 17 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: The small G-protein RalA promotes progression and metastasis of triple-negative breast cancer. aug: au: Thies, Katie A. Cole, Matthew W. Schafer, Rachel E. Spehar, Jonathan M. Richardson, Dillon S. Steck, Sarah A. Das, Manjusri Lian, Arthur W. Ray, Alo Shakya, Reena Knoblaugh, Sue E. Timmers, Cynthia D. Ostrowski, Michael C. Chakravarti, Arnab Sizemore, Gina M. Sizemore, Steven T. affil: Arthur G. James Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, OH, USA sug: subj: Breast Neoplasms Pathology Breast Neoplasms Metabolism Carrier Proteins Metabolism Female Mice Cell Line, Tumor Paclitaxel Therapeutic Use Cell Movement Enzyme Inhibitors Therapeutic Use Neoplasm Metastasis Cell Physiology Prognosis Animal Studies Carrier Proteins Cell Physiology Drug Effects Human Breast Neoplasms Drug Therapy Carrier Proteins Antagonists and Inhibitors Comparative Studies Multicenter Studies Evaluation Research Validation Studies Questionnaires Female ab: Background: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC.Methods: The necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models.Results: Knockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo.Conclusions: Together, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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