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Clinical Investigations |
Departments of Pathology [M. E. M.] and Radiation Oncology [I. K.], Beth Israel Deaconess Medical Center, Department of Pathology, Brigham and Women’s Hospital [M. L.], and the Department of Adult Oncology and the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute [P. S., S. P., M. L., W. R. S.], Harvard Medical School, Boston, Massachusetts 02115
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PTEN can also act as a lipid phosphatase. Specifically, PTEN can dephosphorylate phosphotidylinositol 3,4,5-trisphosphate and phosphotidylinositol 3,4-trisphosphate, which are both direct products of PI3K3 activity (10) . We and others have shown that PTEN can inhibit cell cycle progression and induce a G1 arrest. This function appears to require the lipid phosphatase activity of PTEN, resulting in the negative regulation of the PI3K/Akt signaling pathway (11, 12, 13) . A significant increase in the level of the cell cycle kinase inhibitor p27KIP1 occurs with concomitant decreases in G1 cyclin-dependent kinase activity upon the introduction of PTEN into human glioblastoma U87MG cells, suggesting that p27 may be a target of the PTEN cell cycle arrest pathway (13) . In keeping with these data, heterozygous loss of the murine PTEN gene (mPTEN) leads to an increase in the mitotic index and the Ki-67 staining index in the murine prostate (7) . In addition, PTEN negatively regulates Akt-dependent cell survival (14, 15, 16, 17) . Akt is one of the key regulatory molecules involved in the protection of cells against apoptosis. These data support the idea that PTEN negatively regulates cell growth and/or proliferation through its ability to act as an in vivo phosphoinositide 3-phosphatase, thus negatively regulating the PI3K/Akt signaling pathway.
Germ-line mutations of PTEN have been detected in cases of Cowden disease and Bannayan-Zonana syndrome, two related hamartoma syndromes (18, 19, 20) . Patients with Cowden disease have an elevated risk of various cancers, including breast and thyroid cancer. Alterations of the second PTEN allele have been demonstrated in gastrointestinal polyps in patients with Cowden disease (21) .
Somatic alterations of PTEN are common in certain cell lines and in primary tumors including gliomas (22, 23, 24, 25) , melanoma (26 , 27) , and thyroid (28) and endometrial cancers (29 , 30) . On the other hand, somatic alterations are rare in breast (31) and renal cancer (32) and were not detected in a series of squamous carcinomas from the head and neck (33) . PTEN mutations and allele loss at 10q23 appear to be a late event in glioblastoma, melanoma, and prostate cancer (22, 23, 24, 25, 26 , 34) . In contrast, PTEN alterations are more common in benign tumors than in malignant thyroid tumors (28) and also occur in a proportion of cases of endometrial hyperplasia, a precursor of endometrial carcinoma (35) , suggesting that the genetic alteration may occur at an early stage in these tumors.
Prostate cancer is the most prevalent form of cancer in men in the Western world and is the second most common cause of male cancer deaths in the United States (36) . Pathological stage and Gleason grade are important predictors of prognosis in patients with primary prostate cancer who undergo radical prostatectomy. Prostate cancer, however, is a remarkably heterogeneous disease. Distinguishing tumors associated with a poor outcome at the time of radical prostatectomy is problematic. The molecular mechanisms of prostate carcinogenesis remain poorly understood. LOH of 10q has been reported to occur in prostate cancer with a high frequency (30–60%; Refs. 37 and 38 ), and two distinct, commonly deleted regions have been identified at 10q22–q24 and 10q25, respectively, implying the presence of putative tumor suppressor genes at these loci (38) . Homozygous deletions and somatic mutations of PTEN have been identified in prostate cell lines and tumor specimens (1 , 2 , 34 , 39, 40, 41, 42, 43, 44, 45) . Marked heterogeneity of PTEN alterations has been observed in metastatic prostate cancer tissues (43) . Loss of PTEN expression is more frequently detected in xenografts of cell lines (34) . PTEN may be inactivated by mechanisms other than gene deletion and mutations, including promoter methylation or translational modification (34) . However, other groups failed to detect PTEN methylation in prostate, bladder, and renal cell cancer with LOH of 10q when a PCR-based assay was used (32 , 40) .
In this study, we wanted to assess the extent of loss of the PTEN protein in prostate cancer using immunohistochemistry. We analyzed the pattern of immunohistochemical staining in 109 cases of paraffin-embedded resected prostate cancer using a murine polyclonal antibody to PTEN. Detection of PTEN protein was correlated with the Gleason score and the pathological stage of the tumor, known prognosticators in prostate cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Processing of Cell Lines and Cell Blocks.
DU145, PC-3, and LNCaP prostate cancer cell lines were obtained from the American Type Culture Collection. The U2-OS cell line was a generous gift of W. G. Kaelin (Dana-Farber Cancer Institute). DU145 cells contain one wild-type PTEN allele and a second variant allele (M134L). PC-3 cells have sustained a homozygous deletion of PTEN. LNCaP cells have a deletion of one allele and a mutation of the other PTEN allele, and the genetic state of PTEN has not been characterized in U2-OS cells. LNCaP and PC-3 cells were grown in RPMI 1640 supplemented with D-glucose, HEPES buffer, L-glutamine, PPi, penicillin, streptomycin, and 10% fetal bovine serum. DU145 cells were maintained in DMEM supplemented with penicillin, streptomycin, and 10% fetal bovine serum, and U2-OS cells were maintained in DMEM supplemented with penicillin, streptomycin, and 10% fetal clone (HyClone). All cells were grown on P100 tissue culture dishes at 37°C. LNCaP and PC-3 cells were grown in a 5% CO2 atmosphere, and DU145 and U2-OS cells were grown in a 10% CO2 atmosphere. Cell pellets were created from DU145 and PC-3 cells, fixed in 10% formalin overnight, and then processed in the regular manner for pathology specimens to produce paraffin cell blocks.
Plasmids.
A cDNA fragment of the PTEN gene encoding amino residues 239–403 was amplified by PCR using primers WRSO-56 (5'-GACTGGATCCATGTACTTTGAGTTCCCTCAGCC-3') and WRSO-57 (5'-CGCGGAATTCTCAGACTTTTGTAATTTGTGTATGC-3') from a cDNA library derived from human embryonic kidney 293 cells (51)
. The resulting PCR fragment was isolated, restricted with BamHI and EcoRI, and ligated to similarly restricted pSG5L to produce pSG5L-PTEN (239–403). This cDNA was confirmed by sequencing. The insert from this plasmid was excised and ligated to BamHI/EcoRI-restricted pGEX2T vector to produce pGEX2T-PTEN (239–403) plasmid.
Antibodies.
Recombinant GST-PTEN (239–403) was produced in Escherichia coli and affinity-purified on glutathione-Sepharose beads by conventional methods (52)
. Mice were inoculated with 100 µg of GST-PTEN (239–403) mixed with Freund’s complete adjuvant. Two weeks later, the mice received a subsequent boost of 100 µg of the purified protein in Freund’s incomplete adjuvant. Immune sera (M1) was obtained by orbital sinus puncture.
In Vitro Translation, Immunoprecipitation, and Immunoblotting.
Full-length HA-tagged PTEN protein (HA-PTEN) was produced in vitro by coupled transcription and translation of the pSG5L-PTEN plasmid using the TnT kit (Promega, Madison, WI). Cell extracts were prepared in the following manner. Cells grown on P100 plates were washed twice with PBS and then lysed on the plate in 500 µl of TNN buffer [150 mM NaCl, 50 mM Tris (pH 7.4), and 0.5% NP40] at 4°C for 20 min. Collected extracts were then cleared by centrifugation at 14,000 rpm for 15 min. Immunoprecipitations of in vitro translated products were carried out at 4°C in NET-N buffer [120 mM NaCl, 10 mM EDTA (pH 8.0), 100 M Tris (pH 7.4), and 0.5% NP40] along with 5 µl of in vitro translated PTEN in 250 µl of NET-N. One µl of antiserum was used per immunoprecipitation experiment. Immune complexes were captured on protein A-Sepharose beads (30 µl of 1:1 beads), washed five times with NET-N, and boiled in 1x Laemmli sample buffer. Whole cell extracts or immunoprecipitates were separated by vertical gel electrophoresis on 7.5% gels. Proteins were transferred to Sequi-blot polyvinylidene difluoride membrane (Bio-Rad) by wet transfer in Towbin’s buffer for 6–16 h. Immunoblots were blocked in TBS + 4% milk. M1 was used at a concentration of 1:10,000 in TBS + 4% milk. Alkaline phosphatase-conjugated goat antimouse antibody was the secondary antibody.
Immunohistochemistry.
Five-µm sections were cut from the selected paraffin blocks of prostate tumor and the DU145 and PC-3 cell blocks, mounted on charged glass slides, baked at 60°C for 60 min, deparaffinized, and rehydrated through graded alcohol rinses. Slides were immersed in 10 mM/liter citrate buffer (pH 6.0; Biogenex, San Ramon, CA) and microwaved in a 750 W oven inside a pressure cooker for 30 min. The slides were cooled at room temperature for 15 min and rinsed in tap water. A 1:2000 dilution of M1, the PTEN murine polyclonal antiserum, was applied for 32 min at 37°C. An automated processor (Ventana ES; Ventana Medical Systems, Tuscon, AZ) was used to incubate the slides in blocker (10% normal goat serum and 10% normal horse serum in Ventana diluent) for 8 min, followed by an incubation in secondary antibody conjugated to an avidin-biotin peroxidase complex (antirabbit and antimouse). Finally, 3,3'-diaminobenzidine was used as a substrate to detect bound antibody complex. The slides were counterstained with hematoxylin. Standardization of the incubation and development times allowed an accurate comparison of expression levels in all cases.
Analysis of Immunohistochemical Staining.
Positive cases were defined by the presence of granular, crisp cytoplasmic staining, as seen in the DU145 positive control samples. The cases were initially divided into three groups: (a) positive (the entire tumor showed staining); (b) mixed (both positive and negative cells/glands were present); and (c) negative (no staining was seen in the represented tumor). The grading of PTEN expression was performed without knowledge of the Gleason score or pathological stage. The presence of positive staining in PIN was noted. The cases were then divided into those that showed positive staining (positive and mixed groups) and those with a total absence of staining (negative group).
Statistical Analysis.
We tested for associations between PTEN expression and Gleason score or pathological stage of disease using the Mann-Whitney nonparametric U test, the c2 test, or Fisher’s exact test, as appropriate. All calculations were performed using StatView 4.5 software (Abacus Concepts, Inc., Berkeley, CA).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, left panel). To determine whether M1 might specifically recognize the endogenous PTEN protein, whole cell protein extracts were prepared from U2-OS osteosarcoma cells and DU145 and PC-3 prostate carcinoma cells, separated by electrophoresis, and subjected to immunoblotting with M1 antiserum (Fig. 1
, right panel). M1 recognized a protein species of approximately Mr 58,000 that is present in DU145 and U2-OS cells but is absent in PC-3 cells. PC-3 cells have sustained a biallelic deletion of the PTEN gene, whereas DU145 contains a wild-type PTEN allele and an allele harboring a missense change at codon 134 (M134L). This protein species migrates slightly faster than the in vitro translated HA-PTEN. Taken together, these data indicate that the recognized protein is endogenous PTEN.
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. Thus, sections of cell blocks of DU145 and PC-3 cell lines served as positive and negative controls, respectively. Preimmune serum also served as a negative control.
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7 (79 cases; Table 1
). The cases were divided into two groups: (a) those with either organ-confined disease or disease extends through into the prostate capsule (T1–T3a; 83 cases); and (b) those with seminal vesicle involvement or metastases to the lymph nodes (T3b and T4; 26 cases; Table 2
).
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. The cases were initially divided into three groups: (a) positive (the entire tumor showed staining); (b) mixed (both positive and negative cells/glands were present); and (c) negative (no staining was seen in the represented tumor). Heterogeneous staining of the tumors was present. Seventeen cases (15.6%) were positive (Fig. 3, B1 and B2)
. Seventy cases (64.2%) showed a mixed staining pattern. Specifically, there were areas of tumor that stained positively, whereas other areas of tumor showed negative staining (Fig. 3, C1 and C2)
. The remaining 22 tumors (20.2%) were negative (Fig. 3, D1 and D2)
. The cases were subsequently divided into those that showed positive staining (positive and mixed groups) and those with a total absence of staining (negative group). The results of PTEN expression in each group were compared.
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7, the correlation with a Gleason score 7 was highly significant (P = 0.0004). Loss of PTEN expression also correlated with advanced disease (pathological tumor stage T3c and T4; P = 0.0078). PTEN expression was seen in two of the five tumors where patients had undergone preoperative total androgen ablation. Follow-up for the cohort was too short to give meaningful survival figures because only four deaths had occurred in the study group.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this data set, complete PTEN loss was found to correlate significantly with the presence of high-stage disease (pathological stage T3b and T4; P = 0.0078). Indeed, PTEN mutations and allele loss at 10q23 have been reported to occur as a late event in most, albeit not all, tumors, including prostate cancers (22, 23, 24, 25, 26
, 28
, 34
, 35)
. We also found that loss of PTEN expression correlated significantly with increasing grade of prostate cancer, i.e., Gleason score (P = 0.0081). When cases were divided into those with a Gleason score < 7 or 7, loss of PTEN expression correlated significantly with a Gleason score 7 (P = 0.0004). A cut point between Gleason score 6 and 7 has previously been recommended when compression of the Gleason score is required (55)
. Similarly, PTEN is altered in high-grade gliomas, but not in low-grade gliomas (22
, 23)
. On the other hand, PTEN alteration occurs in all three grades of endometrial cancer (29
, 30)
, and mutation of a germ-line PTEN allele predisposes carriers to breast and thyroid cancer in humans and to a number of malignancies including prostate cancer in mice (7
, 18
, 20 , 56)
. Thus, PTEN appears to play a role in the initiation of certain tumors, including a murine form of prostate cancer, and may play a role in the progression of other tumors such as gliomas and prostate cancer. Although seemingly paradoxical, the role of PTEN loss as an initiating event versus its role as an agent of progression might arise from fundamental differences between tissues with respect to the order of addition of various oncogenic events. For example, the human adult male prostate epithelial cell might not tolerate loss of PTEN unless the loss was first preceded by a permissive mutational event. On the other hand, this paradox, at least with respect to the prostate, might simply reflect upon our current ability, or lack thereof, to detect certain PTEN mutational events. Indeed, in our data set, the vast majority (85%) of tumors had a portion of the tumor in which PTEN staining was absent, in keeping with the marked heterogeneity of PTEN alterations that has been reported previously in metastatic prostate cancer samples (43)
. If it is the PTEN-null portion of the tumor that is destined to become the predominant metastatic clone, then the apparent lack of PTEN mutations in such organ-confined tumors might simply result from a lack of detection by conventional methodologies.
PTEN alterations have also been described in prostate cancer cell lines, xenografts, and tumors (1 , 2 , 34 , 39, 40, 41, 42, 43, 44) . The true number of inactivating events is likely to be greater because the presence of sequence mutations in promoter/regulatory regions was not excluded by these studies. Of interest, there has been no evidence of PTEN promoter methylation in prostate cancers or bladder and renal cancers with 10q LOH using a DNA-based assay (32 , 40) . However, in certain prostate cancer cells, PTEN mRNA was restored after treatment with the demethylating agent 5-azadeoxycytidine (34) . It is possible that methylation of a transcription factor for PTEN may play a role in the regulation of the gene.
Although we did not assess the genetic status of PTEN in our cases, loss of expression as assessed by immunohistochemistry might reflect a majority of the possible mechanisms resulting in PTEN inactivation. These would include direct inactivation by homozygous deletion, nonsense mutation, certain internal deletions, and promoter methylation or indirect inactivation such as loss of a PTEN-directed transcription factor or posttranscriptional modification, such as that which occurs with cdc25, another dual specificity phosphatase (57) . Missense mutations, which do not grossly destabilize the protein product, would not be accounted for by immunohistochemistry.
PTEN appears to function, at least in part, by acting to brake cell cycle progression (11, 12, 13) . We and others (11 , 12) have previously demonstrated that this function appears to require PTEN lipid phosphatase activity, suggesting that cell cycle regulation may result from inhibition of the PI3K pathway. We further demonstrated that activated forms but not wild-type forms of the proto-oncogene Akt were capable of overriding a PTEN-mediated cell cycle block, raising the possibility that Akt might be an important downstream target of PTEN with respect to cell cycle progression (12) . Similar conclusions have been reached with respect to the function of PTEN as a regulator of apoptosis or cell survival (14, 15, 16, 17 , 58) . These data, taken together, suggest the possibility that targeted inhibition of the PI3K/Akt pathway might be of therapeutic value in patients with prostate cancer. We and others (12 , 59) have also shown that cell lines and tumors in which PTEN is lost have elevated levels of activated Akt. Thus, loss of immunohistochemical detection of PTEN might predict for the presence of activated Akt and, in turn, might become useful as a factor predictive of success for therapies directed against this pathway. In general, this type of predictive factor, such as the estrogen receptor, which can predict for the efficacy of a given therapy, such as tamoxifen, has great clinical utility because it directly impacts treatment decisions.
Our results support the candidacy of PTEN as a tumor suppressor gene in prostate cancer progression. Indeed, loss of PTEN expression may be an important negative prognostic indicator. We are currently working on the development of well-characterized rabbit polyclonal or murine monoclonal antibodies that would provide unlimited amounts of antibody capable of reacting with formalin-fixed tissue. It is possible that immunohistochemistry may be the optimal method for evaluating the functional status of PTEN because it would detect a loss of PTEN induced by a majority of the mechanisms through which gene products are inactivated.
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FOOTNOTES |
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1 Supported in part by grants from CaP CURE (to M. L. and W. R. S.) and the United States Army Medical Research and Material Command-Prostate Cancer Research Program (USAMRMC) (to W. R. S.). Part of this work was presented at the United States and Canadian Academy of Pathology meeting held in Boston, Massachusetts in 1998. 
2 To whom requests for reprints should be addressed. Phone: (617) 632-5261; Fax: (617) 632-5417; E-mail: william_sellers{at}dfci.harvard.edu(W. R. S.). E-mail: massimo_loda{at}dfci.harvard.edu (M. L.).
3 The abbreviations used are: PI3K, phosphatidylinositol 3'-kinase; LOH, loss of heterozygosity.; GST, glutathione S-transferase; HA, hemagglutinin; PIN, prostatic intraepithelial neoplasia.
Received 3/11/99. Accepted 7/ 2/99.
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R. Hill, Y. Song, R. D. Cardiff, and T. Van Dyke Heterogeneous Tumor Evolution Initiated by Loss of pRb Function in a Preclinical Prostate Cancer Model Cancer Res., November 15, 2005; 65(22): 10243 - 10254. [Abstract] [Full Text] [PDF]
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D. W. Nelson, H. Cao, Y. Zhu, B. Sunar-Reeder, C. Y.H. Choi, J. D. Faix, J. M. Brown, A. C. Koong, A. J. Giaccia, and Q.-T. Le A Noninvasive Approach for Assessing Tumor Hypoxia in Xenografts: Developing a Urinary Marker for Hypoxia Cancer Res., July 15, 2005; 65(14): 6151 - 6158. [Abstract] [Full Text] [PDF]
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X. Ma, A. C. Ziel-van der Made, B. Autar, H. A. van der Korput, M. Vermeij, P. van Duijn, K. B. Cleutjens, R. de Krijger, P. Krimpenfort, A. Berns, et al. Targeted Biallelic Inactivation of Pten in the Mouse Prostate Leads to Prostate Cancer Accompanied by Increased Epithelial Cell Proliferation but not by Reduced Apoptosis Cancer Res., July 1, 2005; 65(13): 5730 - 5739. [Abstract] [Full Text] [PDF]
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 C Hughes, A Murphy, C Martin, O Sheils, and J O'Leary Molecular pathology of prostate cancer J. Clin. Pathol., July 1, 2005; 58(7): 673 - 684. [Abstract] [Full Text] [PDF]
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Z Culig, H Steiner, G Bartsch, and A Hobisch Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244. [Abstract] [Full Text] [PDF]
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 W. E. Grizzle, D. G. Bostwick, H. Burke, O. W. Tawfik, D. McGregor, J. Cohn, and R. Lieberman Biomarkers in Prostate Cancer Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 196 - 204. [Full Text] [PDF]
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 R. L. Lynch, B. W. Konicek, A. M. McNulty, K. R. Hanna, J. E. Lewis, B. L. Neubauer, and J. R. Graff The Progression of LNCaP Human Prostate Cancer Cells to Androgen Independence Involves Decreased FOXO3a Expression and Reduced p27KIP1 Promoter Transactivation Mol. Cancer Res., March 1, 2005; 3(3): 163 - 169. [Abstract] [Full Text] [PDF]
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G. V. Thomas, S. Horvath, B. L. Smith, K. Crosby, L. A. Lebel, M. Schrage, J. Said, J. De Kernion, R. E. Reiter, and C. L. Sawyers Antibody-Based Profiling of the Phosphoinositide 3-Kinase Pathway in Clinical Prostate Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8351 - 8356. [Abstract] [Full Text] [PDF]
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T. M. Beer, A. Myrthue, M. Garzotto, M. F. O'Hara, R. Chin, B. A. Lowe, M. A. Montalto, C. L. Corless, and W. D. Henner Randomized Study of High-Dose Pulse Calcitriol or Placebo prior to Radical Prostatectomy Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2225 - 2232. [Abstract] [Full Text] [PDF]
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R. Foley, D. Hollywood, and M. Lawler Molecular pathology of prostate cancer: the key to identifying new biomarkers of disease Endocr. Relat. Cancer, September 1, 2004; 11(3): 477 - 488. [Abstract] [Full Text] [PDF]
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S. Kraus, G. Levy, T. Hanoch, Z. Naor, and R. Seger Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells: Role of c-Jun NH2-Terminal Kinase, Protein Kinase B, and Extracellular Signal-Regulated Kinase Pathways Cancer Res., August 15, 2004; 64(16): 5736 - 5744. [Abstract] [Full Text] [PDF]
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G. P. Dasmahapatra, P. Didolkar, M. C. Alley, S. Ghosh, E. A. Sausville, and K. K. Roy In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines Clin. Cancer Res., August 1, 2004; 10(15): 5242 - 5252. [Abstract] [Full Text] [PDF]
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I. Sansal and W. R. Sellers The Biology and Clinical Relevance of the PTEN Tumor Suppressor Pathway J. Clin. Oncol., July 15, 2004; 22(14): 2954 - 2963. [Abstract] [Full Text] [PDF]
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H. Huang, D. C. Muddiman, and D. J. Tindall Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells J. Biol. Chem., April 2, 2004; 279(14): 13866 - 13877. [Abstract] [Full Text] [PDF]
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 C. A. Heinlein and C. Chang Androgen Receptor in Prostate Cancer Endocr. Rev., April 1, 2004; 25(2): 276 - 308. [Abstract] [Full Text] [PDF]
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S. B. Kondapaka, S. S. Singh, G. P. Dasmahapatra, E. A. Sausville, and K. K. Roy Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation Mol. Cancer Ther., November 1, 2003; 2(11): 1093 - 1103. [Abstract] [Full Text] [PDF]
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Y. Tanaka, M. V. Gavrielides, Y. Mitsuuchi, T. Fujii, and M. G. Kazanietz Protein Kinase C Promotes Apoptosis in LNCaP Prostate Cancer Cells through Activation of p38 MAPK and Inhibition of the Akt Survival Pathway J. Biol. Chem., September 5, 2003; 278(36): 33753 - 33762. [Abstract] [Full Text] [PDF]
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S. Rossi, E. Graner, P. Febbo, L. Weinstein, N. Bhattacharya, T. Onody, G. Bubley, S. Balk, and M. Loda Fatty Acid Synthase Expression Defines Distinct Molecular Signatures in Prostate Cancer Mol. Cancer Res., August 1, 2003; 1(10): 707 - 715. [Abstract] [Full Text] [PDF]
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 W. G. Nelson, A. M. De Marzo, and W. B. Isaacs Prostate Cancer N. Engl. J. Med., July 24, 2003; 349(4): 366 - 381. [Full Text] [PDF]
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C. Abate-Shen, W. A. Banach-Petrosky, X. Sun, K. D. Economides, N. Desai, J. P. Gregg, A. D. Borowsky, R. D. Cardiff, and M. M. Shen Nkx3.1; Pten Mutant Mice Develop Invasive Prostate Adenocarcinoma and Lymph Node Metastases Cancer Res., July 15, 2003; 63(14): 3886 - 3890. [Abstract] [Full Text] [PDF]
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Q.-T. Le and A. J. Giaccia HIF-{alpha}, a Gender Independent Transcription Factor Clin. Cancer Res., July 1, 2003; 9(7): 2391 - 2393. [Full Text] [PDF]
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O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen Combined Loss of PTEN and p27 Expression Is Associated with Tumor Cell Proliferation by Ki-67 and Increased Risk of Recurrent Disease in Localized Prostate Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1474 - 1479. [Abstract] [Full Text] [PDF]
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V. Modur, R. Nagarajan, B. M. Evers, and J. Milbrandt FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression. IMPLICATIONS FOR PTEN MUTATION IN PROSTATE CANCER J. Biol. Chem., November 27, 2002; 277(49): 47928 - 47937. [Abstract] [Full Text] [PDF]
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V. Grunwald, L. DeGraffenried, D. Russel, W. E. Friedrichs, R. B. Ray, and M. Hidalgo Inhibitors of mTOR Reverse Doxorubicin Resistance Conferred by PTEN Status in Prostate Cancer Cells Cancer Res., November 1, 2002; 62(21): 6141 - 6145. [Abstract] [Full Text] [PDF]
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T. R. Rebbeck Inherited Genotype and Prostate Cancer Outcomes Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 945 - 952. [Abstract] [Full Text] [PDF]
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M. Fernandez and C. Eng The Expanding Role of PTEN in Neoplasia: A Molecule for All Seasons? : Commentary re: M. A. Davies, et al., Adenoviral-mediated Expression of MMAC/PTEN Inhibits Proliferation and Metastasis of Human Prostate Cancer Cells. Clin. Cancer Res., 8: 1904-1914, 2002. Clin. Cancer Res., June 1, 2002; 8(6): 1695 - 1698. [Abstract] [Full Text] [PDF]
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M. A. Davies, S. J. Kim, N. U. Parikh, Z. Dong, C. D. Bucana, and G. E. Gallick Adenoviral-mediated Expression of MMAC/PTEN Inhibits Proliferation and Metastasis of Human Prostate Cancer Cells Clin. Cancer Res., June 1, 2002; 8(6): 1904 - 1914. [Abstract] [Full Text] [PDF]
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G. O. Hellawell, G. D. H. Turner, D. R. Davies, R. Poulsom, S. F. Brewster, and V. M. Macaulay Expression of the Type 1 Insulin-like Growth Factor Receptor Is Up-Regulated in Primary Prostate Cancer and Commonly Persists in Metastatic Disease Cancer Res., May 1, 2002; 62(10): 2942 - 2950. [Abstract] [Full Text] [PDF]
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L. Zhuang, J. Lin, M. L. Lu, K. R. Solomon, and M. R. Freeman Cholesterol-rich Lipid Rafts Mediate Akt-regulated Survival in Prostate Cancer Cells Cancer Res., April 1, 2002; 62(8): 2227 - 2231. [Abstract] [Full Text] [PDF]
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S. N. Malik, M. Brattain, P. M. Ghosh, D. A. Troyer, T. Prihoda, R. Bedolla, and J. I. Kreisberg Immunohistochemical Demonstration of Phospho-Akt in High Gleason Grade Prostate Cancer Clin. Cancer Res., April 1, 2002; 8(4): 1168 - 1171. [Abstract] [Full Text] [PDF]
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S. R. Chinni and F. H. Sarkar Akt Inactivation Is a Key Event in Indole-3-carbinol-induced Apoptosis in PC-3 Cells Clin. Cancer Res., April 1, 2002; 8(4): 1228 - 1236. [Abstract] [Full Text] [PDF]
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N. Konishi, M. Nakamura, M. Kishi, M. Nishimine, E. Ishida, and K. Shimada Heterogeneous Methylation and Deletion Patterns of the INK4a/ARF Locus Within Prostate Carcinomas Am. J. Pathol., April 1, 2002; 160(4): 1207 - 1214. [Abstract] [Full Text] [PDF]
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 M. E. Grossmann, H. Huang, and D. J. Tindall Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer J Natl Cancer Inst, November 21, 2001; 93(22): 1687 - 1697. [Abstract] [Full Text] [PDF]
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H. Huang, J. C. Cheville, Y. Pan, P. C. Roche, L. J. Schmidt, and D. J. Tindall PTEN Induces Chemosensitivity in PTEN-mutated Prostate Cancer Cells by Suppression of Bcl-2 Expression J. Biol. Chem., October 12, 2001; 276(42): 38830 - 38836. [Abstract] [Full Text] [PDF]
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T. Minaguchi, H. Yoshikawa, K. Oda, T. Ishino, T. Yasugi, T. Onda, S. Nakagawa, K. Matsumoto, K. Kawana, and Y. Taketani PTEN Mutation Located Only Outside Exons 5, 6, and 7 Is an Independent Predictor of Favorable Survival in Endometrial Carcinomas Clin. Cancer Res., September 1, 2001; 7(9): 2636 - 2642. [Abstract] [Full Text] [PDF]
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K. Kimura, M. Markowski, C. Bowen, and E. P. Gelmann Androgen Blocks Apoptosis of Hormone-dependent Prostate Cancer Cells Cancer Res., July 1, 2001; 61(14): 5611 - 5618. [Abstract] [Full Text] [PDF]
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J. R. Graff, J. A. Deddens, B. W. Konicek, B. M. Colligan, B. M. Hurst, H. W. Carter, and J. H. Carter Integrin-linked Kinase Expression Increases with Prostate Tumor Grade Clin. Cancer Res., July 1, 2001; 7(7): 1987 - 1991. [Abstract] [Full Text] [PDF]
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D. J. George, T. F. Shepard, J. Ma, E. Giovannucci, P. W. Kantoff, and M. J. Stampfer PTEN Polymorphism (IVS4) Is Not Associated with Risk of Prostate Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2001; 10(4): 411 - 412. [Full Text]
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Y. Kanamori, J. Kigawa, H. Itamochi, M. Shimada, M. Takahashi, S. Kamazawa, S. Sato, R. Akeshima, and N. Terakawa Correlation between Loss of PTEN Expression and Akt Phosphorylation in Endometrial Carcinoma Clin. Cancer Res., April 1, 2001; 7(4): 892 - 895. [Abstract] [Full Text]
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K. L. Nathanson, R. Omaruddin, S. B. Malkowicz, and T. R. Rebbeck An Intronic Variant in PTEN Is Not Associated with Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., March 1, 2001; 10(3): 277 - 278. [Full Text]
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A. R. Gottschalk, D. Basila, M. Wong, N. M. Dean, C. H. Brandts, D. Stokoe, and D. A. Haas-Kogan p27Kip1 Is Required for PTEN-induced G1 Growth Arrest Cancer Res., March 1, 2001; 61(5): 2105 - 2111. [Abstract] [Full Text]
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G. Kulik, J. P. Carson, T. Vomastek, K. Overman, B. D. Gooch, S. Srinivasula, E. Alnemri, G. Nunez, and M. J. Weber Tumor Necrosis Factor {{alpha}} Induces BID Cleavage and Bypasses Antiapoptotic Signals in Prostate Cancer LNCaP Cells Cancer Res., March 1, 2001; 61(6): 2713 - 2719. [Abstract] [Full Text]
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J.-T. Dong, C.-L. Li, T. W. Sipe, and H. F. Frierson Jr. Mutations of PTEN/MMAC1 in Primary Prostate Cancers from Chinese Patients Clin. Cancer Res., February 1, 2001; 7(2): 304 - 308. [Abstract] [Full Text]
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 C. Abate-Shen and M. M. Shen Molecular genetics of prostate cancer Genes & Dev., October 1, 2000; 14(19): 2410 - 2434. [Full Text]
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G. L. Semenza HIF-1 and human disease: one highly involved factor Genes & Dev., August 15, 2000; 14(16): 1983 - 1991. [Full Text]
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V. Stambolic, M.-S. Tsao, D. Macpherson, A. Suzuki, W. B. Chapman, and T. W. Mak High Incidence of Breast and Endometrial Neoplasia Resembling Human Cowden Syndrome in pten+/- Mice Cancer Res., July 1, 2000; 60(13): 3605 - 3611. [Abstract] [Full Text]
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I. U. Ali Gatekeeper for Endometrium: the PTEN Tumor Suppressor Gene J Natl Cancer Inst, June 7, 2000; 92(11): 861 - 863. [Full Text] [PDF]
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H. Zhong, K. Chiles, D. Feldser, E. Laughner, C. Hanrahan, M.-M. Georgescu, J. W. Simons, and G. L. Semenza Modulation of Hypoxia-inducible Factor 1{{alpha}} Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics Cancer Res., March 1, 2000; 60(6): 1541 - 1545. [Abstract] [Full Text]
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 G. Guanti, N. Resta, C. Simone, F. Cariola, I. Demma, P. Fiorente, and M. Gentile Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis Hum. Mol. Genet., January 22, 2000; 9(2): 283 - 287. [Abstract] [Full Text] [PDF]
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J. A. Gustin, T. Maehama, J. E. Dixon, and D. B. Donner The PTEN Tumor Suppressor Protein Inhibits Tumor Necrosis Factor-induced Nuclear Factor kappa B Activity J. Biol. Chem., July 13, 2001; 276(29): 27740 - 27744. [Abstract] [Full Text] [PDF]
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M. Srivastava, L. Bubendorf, V. Srikantan, L. Fossom, L. Nolan, M. Glasman, X. Leighton, W. Fehrle, S. Pittaluga, M. Raffeld, et al. ANX7, a candidate tumor suppressor gene for prostate cancer PNAS, April 10, 2001; 98(8): 4575 - 4580. [Abstract] [Full Text] [PDF]
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