KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.
Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant of the KLF6 tumor suppressor gene, is associated with increased metastatic potential and poor survival in a cohort of 671 lymph node-negative breast cancer patients. KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal-like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Additionally, KLF6-SV1 loss-of-function studies demonstrated reversion to an epithelial and less invasive phenotype. Combined, these findings implicate KLF6-SV1 as a key driver of breast cancer metastasis that distinguishes between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer.
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Raheleh
R
Hatami
Anieta M
AM
Sieuwerts
Sudeh
S
Izadmehr
Zhong
Z
Yao
Rui Fang
RF
Qiao
Luena
L
Papa
Maxime P
MP
Look
Marcel
M
Smid
Jessica
J
Ohlssen
Alice C
AC
Levine
Doris
D
Germain
David
D
Burstein
Alexander
A
Kirschenbaum
Analisa
A
DiFeo
John A
JA
Foekens
Goutham
G
Narla
D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D051879:Twist-Related Protein 1; D023041:Xenograft Model Antitumor Assays
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1