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

Obi L. Griffith; Szeman Ruby Chan; Malachi Griffith; Kilannin Krysiak; Zachary L. Skidmore; Jasreet Hundal; Julie A. Allen; Cora D. Arthur; Daniele Runci; Mattia Bugatti; Alexander P. Miceli; Heather Schmidt; Lee Trani; Krishna Latha Kanchi; Christopher A. Miller; David E. Larson; Robert S. Fulton; William Vermi; Richard K. Wilson; Robert D. Schreiber; Elaine R. Mardis

doi:10.1016/j.celrep.2016.08.076

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

Obi L. Griffith, Szeman Ruby Chan, Malachi Griffith, Kilannin Krysiak, Zachary L. Skidmore, Jasreet Hundal, Julie A. Allen, Cora D. Arthur, Daniele Runci, Mattia Bugatti, Alexander P. Miceli, Heather Schmidt, Lee Trani, Krishna Latha Kanchi, Christopher A. Miller, David E. Larson, Robert S. Fulton, William Vermi, Richard K. Wilson, Robert D. SchreiberElaine R. Mardis

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18 Scopus citations

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.

Original language	English
Pages (from-to)	249-260
Number of pages	12
Journal	Cell Reports
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2016.08.076
State	Published - Sep 27 2016

Keywords

PRLR
STAT1
breast cancer
estrogen-receptor positive
luminal
mouse model
whole genome sequencing

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10.1016/j.celrep.2016.08.076

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Griffith, O. L., Chan, S. R., Griffith, M., Krysiak, K., Skidmore, Z. L., Hundal, J., Allen, J. A., Arthur, C. D., Runci, D., Bugatti, M., Miceli, A. P., Schmidt, H., Trani, L., Kanchi, K. L., Miller, C. A., Larson, D. E., Fulton, R. S., Vermi, W., Wilson, R. K., ... Mardis, E. R. (2016). Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas. Cell Reports, 17(1), 249-260. https://doi.org/10.1016/j.celrep.2016.08.076

@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 = "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",

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Griffith, OL, Chan, SR, Griffith, M , Krysiak, K, Skidmore, ZL, Hundal, J, Allen, JA, Arthur, CD, Runci, D, Bugatti, M, Miceli, AP, Schmidt, H, Trani, L, Kanchi, KL, Miller, CA, Larson, DE, Fulton, RS, Vermi, W, Wilson, RK, Schreiber, RD & Mardis, ER 2016, 'Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas', Cell Reports, vol. 17, no. 1, pp. 249-260. https://doi.org/10.1016/j.celrep.2016.08.076

TY - JOUR

T1 - Truncating Prolactin Receptor Mutations Promote Tumor Growth in Murine Estrogen Receptor-Alpha Mammary Carcinomas

AU - Griffith, Obi L.

AU - Chan, Szeman Ruby

AU - Griffith, Malachi

AU - Krysiak, Kilannin

AU - Skidmore, Zachary L.

AU - Hundal, Jasreet

AU - Allen, Julie A.

AU - Arthur, Cora D.

AU - Runci, Daniele

AU - Bugatti, Mattia

AU - Miceli, Alexander P.

AU - Schmidt, Heather

AU - Trani, Lee

AU - Kanchi, Krishna Latha

AU - Miller, Christopher A.

AU - Larson, David E.

AU - Fulton, Robert S.

AU - Vermi, William

AU - Wilson, Richard K.

AU - Schreiber, Robert D.

AU - Mardis, Elaine R.

PY - 2016/9/27

Y1 - 2016/9/27

N2 - 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.

AB - 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.

KW - PRLR

KW - STAT1

KW - breast cancer

KW - estrogen-receptor positive

KW - luminal

KW - mouse model

KW - whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=84989884624&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.08.076

DO - 10.1016/j.celrep.2016.08.076

M3 - Article

C2 - 27681435

AN - SCOPUS:84989884624

SN - 2211-1247

VL - 17

SP - 249

EP - 260

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

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Keywords

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