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J. Biol. Chem., Vol. 277, Issue 32, 29132-29138, August 9, 2002
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From the The mechanism by which gap junction proteins,
connexins, act as potent tumor suppressors remains poorly
understood. In this study human breast tumor cells were found to
exhibit diverse gap junction phenotypes including (a) undetectable Cx43
and no intercellular communication (HBL100); (b) low levels of Cx43 and
sparse intercellular communication (MDA-MB-231); and (c) significant
levels of Cx43 and moderate intercellular communication (Hs578T).
Although retroviral delivery of Cx43 and Cx26 cDNAs to MDA-MB-231
cells did not achieve an expected substantial rescue of intercellular
communication, overexpression of connexin genes did result in a
dramatic suppression of tumor growth when connexin-expressing
MDA-MB-231 cells were implanted into the mammary fat pad of nude mice.
Subsequent immunolocalization studies on xenograph sections revealed
only cytoplasmic stores of Cx43 and no detectable gap junctions.
Moreover, DNA array and Western blot analysis demonstrated that
overexpression of Cx43 or Cx26 in MDA-MB-231 cells
down-regulated fibroblast growth factor receptor-3. Surprisingly, these
results suggest that Cx43 and Cx26 induce their tumor-suppressing
properties by a mechanism that is independent of significant gap
junctional intercellular communication and possibly through the
down-regulation of key genes involved in tumor growth. Moreover, our
studies show that retroviruses are effective vehicles for delivering
connexins to human breast tumor cells, facilitating potential gene
therapy applications.
Retroviral Delivery of Connexin Genes to Human Breast Tumor Cells
Inhibits in Vivo Tumor Growth by a Mechanism That Is
Independent of Significant Gap Junctional Intercellular
Communication*
,,,,¶
Department of Anatomy and Cell Biology,
University of Western Ontario, London, Ontario N6A 5C1, Canada and the
§ Departments of Medicine, Pharmacology, and Therapeutics
and the McGill Centre for Translational Research in Cancer, Lady
Davis Institute for Medical Research, McGill University, Montreal,
Quebec H3T 1E2, Canada
*
This work was supported by grants from the McGill Centre for
Translational Research in Cancer and the Canadian Breast Cancer Research Initiative (to D. W. L. and M. A. J.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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