Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers.
OBJECTIVE
Rho family members are small GTPases that are known to regulate malignant transformation and motility of cancer cells. The activities of Rhos are regulated by molecules such as guanine nucleotide dissociation inhibitors (GDIs). This study determined the levels of expression and the distribution of Rho-A, -B, -C, and -G, and Rho-6, -7, and -8, as well as Rho-GDI-beta, and Rho-GDI-gamma, in breast cancer and assessed their prognostic value.


METHODS
The distribution and location of Rhos and RhoGDIs were assessed using immunohistochemical staining of frozen sections. The levels of transcripts of these molecules were determined using a real-time quantitative PCR. Levels of expression were analyzed against nodal involvement and distant metastasis, grade, and survival over a 6-year follow-up period.


RESULTS
The levels of Rho-C, Rho-6, and Rho-G were significantly higher in breast cancer tissues (n = 120) than in background normal tissues (n = 32). However, the level of Rho-A and -B and rho-7 and -8 was found to be similar in tumor and normal tissues. Immunohistochemical staining revealed the high level of staining of Rho-C protein in tumor cells. The levels of Rho-GDI-gamma transcripts were found to be significantly lower in tumor tissues than in normal tissues (P < 0.05 and P < 0.001, respectively). Node-positive tumors have significantly higher levels of Rho-C and Rho-G, and lower levels of Rho-GDI and Rho-GDI-gamma transcripts, than do node-negative tumors. Significantly higher levels of Rho-C and Rho-G were seen in patients who died of breast cancer than in those who remained disease free. Patients with recurrent disease, with metastasis or who died of breast cancer, also exhibited higher levels of Rho-6 but lower levels of Rho-GDI-gamma. Higher-grade tumors were also associated with low levels of Rho-GDI and Rho-GDI-gamma.


CONCLUSIONS
Raised levels of Rho-C, Rho-G and Rho-6 and reduced expression of Rho-GDI and -GDI-gamma in breast tumor tissues are correlated with the nodal involvement and metastasis. This suggests that the expression of Rhos and Rho-GDIs in breast cancer is unbalanced and that this disturbance has clinical significance in breast cancer.
Jiang
Wen G
WG
University Department of Surgery, University of Wales College of Medicine, Cardiff, United Kingdom. jiangw@cf.ac.uk
Watkins
Gareth
G
Lane
Jane
J
Cunnick
Giles H
GH
Douglas-Jones
Anthony
A
Mokbel
Kefah
K
Mansel
Robert E
RE
D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary / Q000378:metabolism; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D018076:DNA, Complementary; D012333:RNA, Messenger; D012313:RNA; D020741:rho GTP-Binding Proteins