| Literature DB >> 27681435 |
Obi L Griffith1, Szeman Ruby Chan2, Malachi Griffith3, Kilannin Krysiak4, Zachary L Skidmore5, Jasreet Hundal5, Julie A Allen2, Cora D Arthur2, Daniele Runci2, Mattia Bugatti6, Alexander P Miceli2, Heather Schmidt5, Lee Trani5, Krishna-Latha Kanchi5, Christopher A Miller4, David E Larson7, Robert S Fulton7, William Vermi8, Richard K Wilson9, Robert D Schreiber10, Elaine R Mardis11.
Abstract
Estrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1(-/-) mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1(-/-) primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1(-/-) mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation.Entities:
Keywords: PRLR; STAT1; breast cancer; estrogen-receptor positive; luminal; mouse model; whole genome sequencing
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Year: 2016 PMID： 27681435 PMCID： PMC5557050 DOI： 10.1016/j.celrep.2016.08.076
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423