Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.
Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.
Antti
A
Arjonen
Riina
R
Kaukonen
Elina
E
Mattila
Pegah
P
Rouhi
Gunilla
G
Högnäs
Harri
H
Sihto
Bryan W
BW
Miller
Jennifer P
JP
Morton
Elmar
E
Bucher
Pekka
P
Taimen
Reetta
R
Virtakoivu
Yihai
Y
Cao
Owen J
OJ
Sansom
Heikki
H
Joensuu
Johanna
J
Ivaska
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D005260:Female; D015870:Gene Expression; D006801:Humans; D016023:Integrins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation; D015027:Zebrafish
D016023:Integrins; C498718:MYO10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009218:Myosins