Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance

Christina M. Medina-Ramirez, Sumanta Goswami, Tatiana Smirnova, Daniel Bamira, Benjamin Benson, Neal Ferrick, Jeffrey Segall, Jeffrey W. Pollard, Richard N. Kitsis

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Apoptosis repressor with caspase recruitment domain (ARC) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. Although expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiologic functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, in which endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was shown to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors and invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells.

Original languageEnglish (US)
Pages (from-to)7705-7715
Number of pages11
JournalCancer research
Volume71
Issue number24
DOIs
StatePublished - Dec 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Medina-Ramirez, C. M., Goswami, S., Smirnova, T., Bamira, D., Benson, B., Ferrick, N., Segall, J., Pollard, J. W., & Kitsis, R. N. (2011). Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer research, 71(24), 7705-7715. https://doi.org/10.1158/0008-5472.CAN-11-2192