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FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.


ABSTRACT: Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

SUBMITTER: Ferraro GB 

PROVIDER: S-EPMC8223728 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

Ferraro Gino B GB   Ali Ahmed A   Luengo Alba A   Kodack David P DP   Deik Amy A   Abbott Keene L KL   Bezwada Divya D   Blanc Landry L   Prideaux Brendan B   Jin Xin X   Posada Jessica M JM   Chen Jiang J   Chin Christopher R CR   Amoozgar Zohreh Z   Ferreira Raphael R   Chen Ivy X IX   Naxerova Kamila K   Ng Christopher C   Westermark Anna M AM   Duquette Mark M   Roberge Sylvie S   Lindeman Neal I NI   Lyssiotis Costas A CA   Nielsen Jens J   Housman David E DE   Duda Dan G DG   Brachtel Elena E   Golub Todd R TR   Cantley Lewis C LC   Asara John M JM   Davidson Shawn M SM   Fukumura Dai D   Dartois Véronique A VA   Clish Clary B CB   Jain Rakesh K RK   Vander Heiden Matthew G MG  

Nature cancer 20210401 4


Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus ext  ...[more]

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