title: PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.
abstract: 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.
authors.affiliation: Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Pai
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hirota
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Hosobe
authors.forename: Taisei
authors.initials: T
authors.lastname: Tsukada
authors.forename: Kunio
authors.initials: K
authors.lastname: Miura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takano
authors.forename: Ken
authors.initials: K
authors.lastname: Saito
authors.forename: Therese
authors.initials: T
authors.lastname: Commes
authors.forename: David
authors.initials: D
authors.lastname: Piquemal
authors.forename: Misako
authors.initials: M
authors.lastname: Watabe
authors.forename: Steven
authors.initials: S
authors.lastname: Gross
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jodi
authors.initials: J
authors.lastname: Huggenvik
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: 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
chemical_list: 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