Increased levels of the HER1 adaptor protein Rukl/CIN85 contribute to breast cancer malignancy.
The adaptor protein regulator for ubiquitous kinase/c-Cbl-interacting protein of 85kDa (Ruk/CIN85) was found to modulate HER1/EGFR signaling and processes like cell adhesion and apoptosis. Although these features imply a role in carcinogenesis, it is so far unknown how and by which molecular mechanisms Ruk/CIN85 could affect a certain tumor phenotype. By analyzing samples from breast cancer patients, we found high levels of Ruk(l)/CIN85 especially in lymph node metastases from patients with invasive breast adenocarcinomas, suggesting that Ruk(l)/CIN85 contributes to malignancy. Expression of Ruk(l)/CIN85 in weakly invasive breast adenocarcinoma cells deficient of Ruk(l)/CIN85 indeed converted them into more malignant cells. In particular, Ruk(l)/CIN85 reduced the growth rate, decreased cell adhesion, enhanced anchorage-independent growth, increased motility in both transwell migration and wound healing assays as well as affected the response to epidermal growth factor. Thereby, Ruk(l)/CIN85 led to a more rapid and prolonged epidermal growth factor-dependent activation of Src, Akt and ERK1/2 and treatment with the Src inhibitor PP2 and the PI3K inhibitor LY294002 abolished the Ruk(l)/CIN85-dependent changes in cell motility. Together, this study indicates that high levels of Ruk(l)/CIN85 contribute to the conversion of breast adenocarcinoma cells into a more malignant phenotype via modulation of the Src/Akt pathway.
Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Ukraine.
Anatoliy
A
Samoylenko
Bozhena
B
Vynnytska-Myronovska
Nadiya
N
Byts
Nina
N
Kozlova
Olga
O
Basaraba
Ganna
G
Pasichnyk
Kseniya
K
Palyvoda
Yaroslav
Y
Bobak
Maryna
M
Barska
Oksana
O
Mayevska
Yuriy
Y
Rzhepetsky
Halyna
H
Shuvayeva
Valeriy
V
Lyzogubov
Vasyl
V
Usenko
Volodymyr
V
Savran
Nataliya
N
Volodko
Vladimir
V
Buchman
Thomas
T
Kietzmann
Lyudmyla
L
Drobot
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C433810:SH3KBP1 protein, human; D015688:Oncogene Protein pp60(v-src); D051057:Proto-Oncogene Proteins c-akt