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

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

doi:10.1158/0008-5472.can-14-1188

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.

Highlights

Metastasis can occur at the very early stages of cancer disease, especially in the form of micrometastatic lesions [1, 2]
Generation of a lung met–derived breast tumor model On the basis of the previously developed human-in-mouse triple-negative breast tumor models that exhibited spontaneous pulmonary micrometastases [5], we term these primary tumor models as "parental" models, such as metastatic-1 (M1parental), which belongs to the basal-like subtype
A second breast tumor xenograft model was established as M1 lung metastasis–derived mammary tumor model, termed as "M1-met–derived", in contrast to the normally passaged M1-parental breast tumor model (Fig. 1A), both grown in the mouse mammary fat pads to exclude the effects of different microenvironments between the primary and distant sites

Summary

Introduction

Metastasis can occur at the very early stages of cancer disease, especially in the form of micrometastatic lesions [1, 2]. The multistep process of metastasis comprises tumor cell invasion to surrounding tissue, intravasation to vascular or lymphatic structures, survival in circulation, homing and extravasation to distant organs, and colonization with distant. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

Methods

Results

Conclusion