Down-regulation of the oncogene cyclin D1 increases migratory capacity in breast cancer and is linked to unfavorable prognostic features.
The oncogene cyclin D1 is highly expressed in many breast cancers and, despite its proliferation-activating properties, it has been linked to a less malignant phenotype. To clarify this observation, we focused on two key components of malignant behavior, migration and proliferation, and observed that quiescent G(0)/G(1) cells display an increased migratory capacity compared to cycling cells. We also found that the down-regulation of cyclin D1 in actively cycling cells significantly increased migration while also decreasing proliferation. When analyzing a large set of premenopausal breast cancers, we observed an inverse proliferation-independent link between cyclin D1 and tumor size and recurrence, suggesting that this protein might abrogate infiltrative malignant behavior in vivo. Finally, gene expression analysis after cyclin D1 down-regulation by siRNA confirmed changes in processes associated with migration and enrichment of our gene set in a metastatic poor prognosis signature. This novel function of cyclin D1 illustrates the interplay between tumor proliferation and migration and may explain the attenuation of malignant behavior in breast cancers with high cyclin D1 levels.
Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, UMAS, Sweden.
Sophie
S
Lehn
Nicholas P
NP
Tobin
Pontus
P
Berglund
Kristina
K
Nilsson
Andrew H
AH
Sims
Karin
K
Jirström
Pirkko
P
Härkönen
Rebecca
R
Lamb
Göran
G
Landberg
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D019938:Cyclin D1