Genome-wide
copy number analyses of human cancers identified a frequent 5p13 amplification in several
solid tumour types, including
lung (56%),
ovarian (38%),
breast (32%),
prostate (37%) and
melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and
loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent
oncogene. Physically, GOLPH3 localizes to the
trans-Golgi network and interacts with components of the retromer complex, which in
yeast has been linked to target of
rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates
cell size, enhances growth-factor-induced
mTOR (also known as
FRAP1) signalling in human cancer cells, and alters the response to an
mTOR inhibitor in vivo. Thus, genomic and
genetic, biological, functional and biochemical data in
yeast and humans establishes GOLPH3 as a new
oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to
rapamycin, a cancer
drug in clinical use.
