| 1. |
- Maurer, Matthew, et al.
(författare)
-
3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma
- 2009
-
Ingår i: Cancer Research. - 1538-7445. ; 69:15, s. 306-6299
-
Tidskriftsartikel (refereegranskat)abstract
- Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP(3)). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP(3) recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308. We show that total PDK1 protein and mRNA were overexpressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to AKT, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer.
|
|
| 2. |
- Chen, Yilun, et al.
(författare)
-
PTEN and NEDD4 in Human Breast Carcinoma.
- 2016
-
Ingår i: Pathology and Oncology Research. - : Springer Science and Business Media LLC. - 1532-2807 .- 1219-4956. ; 22:1, s. 41-47
-
Tidskriftsartikel (refereegranskat)abstract
- PTEN is an important tumor suppressor gene that antagonizes the oncogenic PI3K/AKT signaling pathway and has functions in the nucleus for maintaining genome integrity. Although PTEN inactivation by mutation is infrequent in breast cancer, transcript and protein levels are deficient in >25 % of cases. The E3 ubiquitin ligase NEDD4 (also known as NEDD4-1) has been reported to negatively regulate PTEN protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder, but its effect on PTEN in the breast has not been studied extensively. To investigate whether NEDD4 contributes to low PTEN levels in human breast cancer, we analyzed the expression of these proteins by immunohistochemistry across a large Swedish cohort of breast tumor specimens, and their transcript expression levels by microarrays. For both NEDD4 and PTEN, their transcript expression was significantly correlated to their protein expression. However, comparing NEDD4 expression to PTEN expression, either no association or a positive correlation was observed at the protein and transcript levels. This unexpected observation was further corroborated in two independent breast cancer cohorts from The Netherlands Cancer Institute and The Cancer Genome Atlas. Our results suggest that NEDD4 is not responsible for the frequent down-regulation of the PTEN protein in human breast carcinoma.
|
|
| 3. |
- Pappas, Kyrie, et al.
(författare)
-
p53 maintains baseline expression of multiple tumor suppressor genes
- 2017
-
Ingår i: Molecular Cancer Research. - 1541-7786. ; 15:8, s. 1051-1062
-
Tidskriftsartikel (refereegranskat)abstract
- TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer.
|
|
| 4. |
- Saal, Lao, et al.
(författare)
-
Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity
- 2007
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:18, s. 7564-7569
-
Tidskriftsartikel (refereegranskat)abstract
- Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (P13K) pathway is frequently activated in solid tumors; however, currently, no reliable test for P13K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of P13K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (IBC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-P13K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant P13K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve.
|
|
| 5. |
- She, Qing Bai, et al.
(författare)
-
Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer
- 2016
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 16:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.
|
|
