RCP is a human breast cancer-promoting gene with Ras-activating function.
Aggressive forms of cancer are often defined by recurrent chromosomal alterations, yet in most cases, the causal or contributing genetic components remain poorly understood. Here, we utilized microarray informatics to identify candidate oncogenes potentially contributing to aggressive breast cancer behavior. We identified the Rab-coupling protein RCP (also known as RAB11FIP1), which is located at a chromosomal region frequently amplified in breast cancer (8p11-12) as a potential candidate. Overexpression of RCP in MCF10A normal human mammary epithelial cells resulted in acquisition of tumorigenic properties such as loss of contact inhibition, growth-factor independence, and anchorage-independent growth. Conversely, knockdown of RCP in human breast cancer cell lines inhibited colony formation, invasion, and migration in vitro and markedly reduced tumor formation and metastasis in mouse xenograft models. Overexpression of RCP enhanced ERK phosphorylation and increased Ras activation in vitro. As these results indicate that RCP is a multifunctional gene frequently amplified in breast cancer that encodes a protein with Ras-activating function, we suggest it has potential importance as a therapeutic target. Furthermore, these studies provide new insight into the emerging role of the Rab family of small G proteins and their interacting partners in carcinogenesis.
Zhang
Jinqiu
J
Stem Cell and Developmental Biology Program, Genome Institute of Singapore, Singapore.
Liu
Xuejing
X
Datta
Arpita
A
Govindarajan
Kunde
K
Tam
Wai Leong
WL
Han
Jianyong
J
George
Joshy
J
Wong
Christopher
C
Ramnarayanan
Kalpana
K
Phua
Tze Yoong
TY
Leong
Wan Yee
WY
Chan
Yang Sun
YS
Palanisamy
Nallasivam
N
Liu
Edison Tak-Bun
ET
Karuturi
Krishna Murthy
KM
Lim
Bing
B
Miller
Lance David
LD
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019295:Computational Biology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009857:Oncogenes; D010766:Phosphorylation; D034622:RNA Interference; D020691:rab GTP-Binding Proteins / Q000502:physiology; D000099193:rab11 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D048049:Extracellular Signal-Regulated MAP Kinases; D008565:Membrane Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C488966:RAB11FIP1 protein, human; C509763:Rab25 protein, human