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Cell Rep. 2016 Sep 27;17(1):249-260. doi: 10.1016/j.celrep.2016.08.076.

Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, 4921 Parkview Pl., St. Louis, MO 63110, USA.
2
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
3
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Siteman Cancer Center, Washington University School of Medicine, 4921 Parkview Pl., St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
4
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
5
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
6
Section of Pathology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
7
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Department of Genetics, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
8
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA; Section of Pathology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
9
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, 4921 Parkview Pl., St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
10
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 425 S Euclid Ave., St. Louis, MO 63110, USA. Electronic address: schreiber@immunology.wustl.edu.
11
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA; Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, 4921 Parkview Pl., St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA. Electronic address: emardis@wustl.edu.

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

PMID:
27681435
PMCID:
PMC5557050
DOI:
10.1016/j.celrep.2016.08.076
[Indexed for MEDLINE]
Free PMC Article

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