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

29 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bockhorn, J., Prat, A., Chang, Y. F., Liu, X., Huang, S., Shang, M., Nwachukwu, C., Gomez-Vega, M. J., Harrell, J. C., Olopade, O. I., Perou, C. M., & Liu, H. (2014). Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models. Cancer research, 74(24), 7406-7417. https://doi.org/10.1158/0008-5472.CAN-14-1188