Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas.
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.
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.
Obi L
OL
Griffith
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
Szeman Ruby
SR
Chan
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.
Malachi
M
Griffith
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.
Kilannin
K
Krysiak
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
Zachary L
ZL
Skidmore
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
Jasreet
J
Hundal
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
Julie A
JA
Allen
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
Cora D
CD
Arthur
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
Daniele
D
Runci
Section of Pathology, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
Mattia
M
Bugatti
Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, USA.
Alexander P
AP
Miceli
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
Heather
H
Schmidt
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
Lee
L
Trani
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave., St. Louis, MO 63108, USA.
Krishna-Latha
KL
Kanchi
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.
Christopher A
CA
Miller
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.
David E
DE
Larson
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.
Robert S
RS
Fulton
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.
William
W
Vermi
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.
Richard K
RK
Wilson
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.
Robert D
RD
Schreiber
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.
Elaine R
ER
Mardis
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011981:Receptors, Prolactin / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D011981:Receptors, Prolactin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse
PRLR; STAT1; breast cancer; estrogen-receptor positive; luminal; mouse model; whole genome sequencing
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