Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models

Jessica Bockhorn, Aleix Prat, Ya Fang Chang, Xia Liu, Simo Huang, Meng Shang, Chika Nwachukwu, Maria J. Gomez-Vega, J. Chuck Harrell, Olufunmilayo I. Olopade, Charles M. Perou, Huiping Liu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.

Original languageEnglish (US)
Pages (from-to)7406-7417
Number of pages12
JournalCancer Research
Volume74
Issue number24
DOIs
StatePublished - Dec 15 2014
Externally publishedYes

Fingerprint

Breast Neoplasms
Neoplasm Metastasis
Lung
Epigenomics
Breast
Neoplasm Micrometastasis
Epithelial-Mesenchymal Transition
Heterografts
Genes
Adipose Tissue
Neoplasms
Cell Proliferation
Phenotype
Survival
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models. / Bockhorn, Jessica; Prat, Aleix; Chang, Ya Fang; Liu, Xia; Huang, Simo; Shang, Meng; Nwachukwu, Chika; Gomez-Vega, Maria J.; Harrell, J. Chuck; Olopade, Olufunmilayo I.; Perou, Charles M.; Liu, Huiping.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7406-7417.

Research output: Contribution to journalArticle

Bockhorn, J, Prat, A, Chang, YF, Liu, X, Huang, S, Shang, M, Nwachukwu, C, Gomez-Vega, MJ, Harrell, JC, Olopade, OI, Perou, CM & Liu, H 2014, 'Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models', Cancer Research, vol. 74, no. 24, pp. 7406-7417. https://doi.org/10.1158/0008-5472.CAN-14-1188
Bockhorn, Jessica ; Prat, Aleix ; Chang, Ya Fang ; Liu, Xia ; Huang, Simo ; Shang, Meng ; Nwachukwu, Chika ; Gomez-Vega, Maria J. ; Harrell, J. Chuck ; Olopade, Olufunmilayo I. ; Perou, Charles M. ; Liu, Huiping. / Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models. In: Cancer Research. 2014 ; Vol. 74, No. 24. pp. 7406-7417.
@article{1085a7e8484f4aea9d4892e5e67b708e,
title = "Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models",
abstract = "Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.",
author = "Jessica Bockhorn and Aleix Prat and Chang, {Ya Fang} and Xia Liu and Simo Huang and Meng Shang and Chika Nwachukwu and Gomez-Vega, {Maria J.} and Harrell, {J. Chuck} and Olopade, {Olufunmilayo I.} and Perou, {Charles M.} and Huiping Liu",
year = "2014",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-14-1188",
language = "English (US)",
volume = "74",
pages = "7406--7417",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",

}

TY - JOUR

T1 - Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models

AU - Bockhorn, Jessica

AU - Prat, Aleix

AU - Chang, Ya Fang

AU - Liu, Xia

AU - Huang, Simo

AU - Shang, Meng

AU - Nwachukwu, Chika

AU - Gomez-Vega, Maria J.

AU - Harrell, J. Chuck

AU - Olopade, Olufunmilayo I.

AU - Perou, Charles M.

AU - Liu, Huiping

PY - 2014/12/15

Y1 - 2014/12/15

N2 - Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.

AB - Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.

UR - http://www.scopus.com/inward/record.url?scp=84918510448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84918510448&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-1188

DO - 10.1158/0008-5472.CAN-14-1188

M3 - Article

C2 - 25339353

AN - SCOPUS:84918510448

VL - 74

SP - 7406

EP - 7417

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 24

ER -