RGS-GAIP-interacting protein controls breast cancer progression.
Although the importance of RGS-GAIP-interacting protein (GIPC) in the biology of malignant cells is well known, the molecular mechanism of GIPC in the inhibition of tumor progression has not been identified. This study focused on elucidating the molecular role of GIPC in breast cancer progression. By using a human breast tumor specimen, an in vivo mouse model, and breast cancer cell lines, we showed for the first time that GIPC is involved in breast cancer progression through regulation of breast cancer cell proliferation, survival, and invasion. Furthermore, we found that the Akt/Mdm2/p53 axis, insulin-like growth factor-1 receptor, matrix metalloproteinase-9, and Cdc42 were downstream of GIPC signaling in breast cancer cells. Moreover, we showed that wild-type p53 reduced GIPC-induced breast cancer cell survival, whereas mutant p53 inhibited GIPC-induced cell invasion. Finally, we demonstrated that an N-myristoylated GIPC peptide (CR1023, N-myristoyl-PSQSSSEA) capable of blocking the PDZ domain of GIPC successfully inhibited MDA-MB-231 cell proliferation, survival, and further in vivo tumor growth. Taken together, these findings demonstrate the importance of GIPC in breast tumor progression, which has a potentially significant impact on the development of therapies against many common cancers expressing GIPC, including breast and renal cancer.
Department of Biochemistry and Molecular Biology, Gugg 13-21C, Mayo Clinic College of Medicine, 200 First St. S.W., Rochester, MN 55905, USA.
Ling
L
Wang
Julie S
JS
Lau
Chitta Ranjan
CR
Patra
Ying
Y
Cao
Santanu
S
Bhattacharya
Shamit
S
Dutta
Debashis
D
Nandy
Enfeng
E
Wang
Chamila N
CN
Rupasinghe
Pawan
P
Vohra
Mark R
MR
Spaller
Debabrata
D
Mukhopadhyay
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D054731:PDZ Domains; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C492009:GIPC1 protein, human; D017451:Receptors, Somatomedin; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D020780:Matrix Metalloproteinase 9; D020764:cdc42 GTP-Binding Protein