PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.
Bandyopadhyay
Sucharita
S
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
Pai
Sudha K
SK
Hirota
Shigeru
S
Hosobe
Sadahiro
S
Tsukada
Taisei
T
Miura
Kunio
K
Takano
Yukio
Y
Saito
Ken
K
Commes
Therese
T
Piquemal
David
D
Watabe
Misako
M
Gross
Steven
S
Wang
Ying
Y
Huggenvik
Jodi
J
Watabe
Kounosuke
K
D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C494929:PTEN protein, human