HIF1A signaling selectively supports proliferation of breast cancer in the brain.

Autor:	Ebright RY; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Zachariah MA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, 39216, USA., Micalizzi DS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA., Wittner BS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Niederhoffer KL; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Nieman LT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Chirn B; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Wiley DF; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Wesley B; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Shaw B; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Nieblas-Bedolla E; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Atlas L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Szabolcs A; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA., Iafrate AJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA., Toner M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Center for Bioengineering in Medicine, Massachusetts General Hospital and Harvard Medical School, and Shriners Hospital for Children, Boston, MA, 02114, USA., Ting DT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA., Brastianos PK; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA., Haber DA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA. dhaber@mgh.harvard.edu.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. dhaber@mgh.harvard.edu.; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. dhaber@mgh.harvard.edu., Maheswaran S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA. maheswaran@helix.mgh.harvard.edu.; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. maheswaran@helix.mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Dec 09; Vol. 11 (1), pp. 6311. Date of Electronic Publication: 2020 Dec 09.
DOI:	10.1038/s41467-020-20144-w
Abstrakt:	Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.
Databáze:	MEDLINE
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