Functional genomics reveal that the serine synthes... [Nature. 2011] - PubMed result

Functional genomics reveal that the serine synthes...[Nature.2011] - PubMed result: "Nature.2011 Jul 14.doi: 10.1038/nature10350.[Epub ahead of print]Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM.1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Ma*sachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Ma*sachusetts Institute of Technology, Cambridge, Ma*sachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Ma*sachusetts 02142, USA [4] The David H.Koch Institute for Integrative Cancer Research at MIT, 77 Ma*sachusetts Avenue, Cambridge, Ma*sachusetts 02139, USA.

Abstract

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation.RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes.Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse.Using this method, we screened a set of metabolic genes a*sociated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis.Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers.PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux.Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis.We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of О