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Communicated by Suzanne Cory, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia, April 12, 2005 (received for review November 23, 2004)
Abstract
The zinc finger protein LMO4 is overexpressed in a high proportion of breast carcinomas. Here, we report that overexpression of a mouse mammary tumor virus (MMTV)-Lmo4 transgene in the mouse mammary gland elicits hyperplasia and mammary intraepithelial neoplasia or adenosquamous carcinoma in two transgenic strains with a tumor latency of 13–18 months. To investigate cellular processes controlled by LMO4 and those that may be deregulated during oncogenesis, we used RNA interference. Down-regulation of LMO4 expression reduced proliferation of human breast cancer cells and increased differentiation of mouse mammary epithelial cells. Furthermore, small-interfering-RNA-transfected breast cancer cells (MDA-MB-231) had a reduced capacity to migrate and invade an extracellular matrix. Conversely, overexpression of LMO4 in noninvasive, immortalized human MCF10A cells promoted cell motility and invasion. Significantly, in a cohort of 159 primary breast cancers, high nuclear levels of LMO4 were an independent predictor of death from breast cancer. Together, these findings suggest that deregulation of LMO4 in breast epithelium contributes directly to breast neoplasia by altering the rate of cellular proliferation and promoting cell invasion.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: visvader{at}wehi.edu.au.
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Author contributions: E.Y.M.S., G.J.L., and J.E.V. designed research; E.Y.M.S., D.S., B.D., A.S.F., R.L.S., G.J.L., and J.E.V. performed research; E.Y.M.S., D.S., A.S.F., R.L.S., G.J.L., and J.E.V. analyzed data; M.L.B. contributed new reagents/analytic tools; and J.E.V. wrote the paper.
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Abbreviations: siRNA, small interfering RNA; LMO, LIM-only; RNAi, RNA interference; MMTV, mouse mammary tumor virus; MIN, mammary intraepithelial neoplasia; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor.
- Copyright © 2005, The National Academy of Sciences
Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer
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