Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells.
The LIM-only protein, LMO4, is a transcriptional modulator overexpressed in breast cancer. It is oncogenic in murine mammary epithelium and is required for G2/M progression of ErbB2-dependent cells as well as growth and invasion of other breast cancer cell types. However, the mechanisms underlying the oncogenic activity of LMO4 remain unclear. Herein, we show that LMO4 is expressed in all breast cancer subtypes examined and its expression level correlates with the degree of proliferation of such tumours. In addition, we have determined that LMO4 silencing induces G2/M arrest in cells from various breast cancer subtypes, suggesting that LMO4 action in the cell cycle is not restricted to a single breast cancer subtype. This arrest was accompanied by increased cell death, amplification of centrosomes, and formation of abnormal mitotic spindles. Consistent with its ability to positively and negatively regulate the formation of active transcription complexes, overexpression of LMO4 also resulted in an increase in centrosome number. Centrosome amplification has been shown to prolong the G2/M phase of the cell cycle and induce apoptosis; thus, we conclude that supernumerary centrosomes mediate the G2/M arrest and cell death in LMO4-deficient cells. Furthermore, the correlation of centrosome amplification with genomic instability suggests that the impact of dysregulated LMO4 on the centrosome cycle may promote LMO4-induced tumour formation.
Montañez-Wiscovich
Marjorie E
ME
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106-4965, USA.
Shelton
Melissa D
MD
Seachrist
Darcie D
DD
Lozada
Kristen L
KL
Johnson
Emhonta
E
Miedler
John D
JD
Abdul-Karim
Fadi W
FW
Visvader
Jane E
JE
Keri
Ruth A
RA
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D018385:Centrosome / Q000378:metabolism / Q000473:pathology*; D005260:Female; D019398:Genes, BRCA1; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008940:Mitotic Index; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011960:Receptors, Estrogen / Q000172:deficiency; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D014157:Transcription Factors
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