Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer.
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.
Sum
Eleanor Y M
EY
The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, 1G Royal Parade, Parkville VIC 3050, Australia.
Segara
Davendra
D
Duscio
Belinda
B
Bath
Mary L
ML
Field
Andrew S
AS
Sutherland
Robert L
RL
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D017931:DNA Primers; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D007150:Immunohistochemistry; D060588:LIM Domain Proteins; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009517:New South Wales; D034622:RNA Interference; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D014157:Transcription Factors