Endogenous human microRNAs that suppress breast cancer metastasis.
A search for general regulators of cancer metastasis has yielded a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. Here we show that restoring the expression of these microRNAs in malignant cells suppresses lung and bone metastasis by human cancer cells in vivo. Of these microRNAs, miR-126 restoration reduces overall tumour growth and proliferation, whereas miR-335 inhibits metastatic cell invasion. miR-335 regulates a set of genes whose collective expression in a large cohort of human tumours is associated with risk of distal metastasis. miR-335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 and extracellular matrix component tenascin C. Expression of miR-126 and miR-335 is lost in the majority of primary breast tumours from patients who relapse, and the loss of expression of either microRNA is associated with poor distal metastasis-free survival. miR-335 and miR-126 are thus identified as metastasis suppressor microRNAs in human breast cancer.
Tavazoie
Sohail F
SF
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Alarcón
Claudio
C
Oskarsson
Thordur
T
Padua
David
D
Wang
Qiongqing
Q
Bos
Paula D
PD
Gerald
William L
WL
Massagué
Joan
J
D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D012008:Recurrence; D055751:SOXC Transcription Factors; D015996:Survival Rate; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D006609:High Mobility Group Proteins; D035683:MicroRNAs; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D019063:Tenascin; D015534:Trans-Activators