@article{c40a077d53a34c3f888f6ff4c6fc99cd,
title = "Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas",
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.",
keywords = "PRLR, STAT1, breast cancer, estrogen-receptor positive, luminal, mouse model, whole genome sequencing",
author = "Griffith, {Obi L.} and Chan, {Szeman Ruby} and Malachi Griffith and Kilannin Krysiak and Skidmore, {Zachary L.} and Jasreet Hundal and Allen, {Julie A.} and Arthur, {Cora D.} and Daniele Runci and Mattia Bugatti and Miceli, {Alexander P.} and Heather Schmidt and Lee Trani and Kanchi, {Krishna Latha} and Miller, {Christopher A.} and Larson, {David E.} and Fulton, {Robert S.} and William Vermi and Wilson, {Richard K.} and Schreiber, {Robert D.} and Mardis, {Elaine R.}",
note = "Funding Information: We thank the McDonnell Genome Institute{\textquoteright}s Production group for sequence data production; Analysis Pipeline group for developing the automated sequence analysis pipelines; LIMS group for developing tools and software to manage samples and sequencing; and Systems group for providing the IT infrastructure and HPC solutions required for sequencing and analysis. We would also like to thank Nathan Dees and Scott Smith for their help with adapting analysis pipelines for the mouse genome during the early phase of this project. O.L.G. was supported by the National Cancer Institute (NIH NCI K22 CA188163). M.G. was supported by the National Human Genome Research Institute (NIH NHGRI K99 HG007940). This work was funded by grants to R.K.W. from the National Human Genome Research Institute (NIH NHGRI U54 HG003079) and R.D.S from the National Cancer Institute (NIH NCI R01 CA043059) and Bristol-Myers Squibb. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = sep,
day = "27",
doi = "10.1016/j.celrep.2016.08.076",
language = "English",
volume = "17",
pages = "249--260",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}