We are upgrading the repository! The content freeze has been extended to December 11, 2024, when we expect the new repository to become available. New submissions or changes to existing items will not be allowed until after the new website goes live. All content already published will remain publicly available for searching and downloading. Updates will be posted in the Website Upgrade 2024 FAQ in the sidebar Help menu. Reach out to escholarship@umassmed.edu with any questions.
Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells
Authors
Pande, SandhyaBrowne, Gillian
Padmanabhan, Srivatsan
Zaidi, Kaleem
Lian, Jane B.
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
Document Type
Journal ArticlePublication Date
2013-08-01Keywords
AnimalsBinding Sites
Breast Neoplasms
Cell Line, Tumor
Core Binding Factor Alpha 1 Subunit
Core Binding Factor beta Subunit
DNA, Neoplasm
Female
Humans
Male
Mammary Neoplasms, Experimental
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Signal Transduction
Cancer Biology
Cell Biology
Cellular and Molecular Physiology
Neoplasms
Oncology
Metadata
Show full item recordAbstract
The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFbeta-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells.Source
J Cell Physiol. 2013 Aug;228(8):1784-92. doi: 10.1002/jcp.24339. Link to article on publisher's siteDOI
10.1002/jcp.24339Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30282PubMed ID
23389849Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/jcp.24339
Scopus Count
Collections
Related items
Showing items related by title, author, creator and subject.
-
Prostate-specific antigen level, stage or Gleason score: which is best for predicting outcomes after radical prostatectomy, and does it vary by the outcome being measured? Results from Shared Equal Access Regional Cancer Hospital databaseMithal, Prabhakar; Howard, Lauren E.; Aronson, William J.; Kane, Christopher J.; Cooperberg, Matthew R.; Terris, Martha K.; Amling, Christopher L.; Freedland, Stephen J. (2015-04-01)OBJECTIVES: To assess the ability of preoperative prostate-specific antigen level, Gleason score and stage to predict prostate cancer outcomes beyond biochemical recurrence, specifically castration-resistant prostate cancer, metastases and prostate cancer-specific mortality in radical prostatectomy patients. METHODS: We carried out a retrospective study of 2735 men in the Shared Equal Access Regional Cancer Hospital database treated by radical prostatectomy from 1988 to 2011 with data available on pathological stage, grade and preoperative prostate-specific antigen. We used Cox hazards analyses to examine the predictive accuracy (c-index) of the preoperative prostate-specific antigen (log-transformed), path Gleason score ( < /= 7, 3 + 4, 4 + 3 and 8-10) and path stage grouping (pT2 negative margins; pT2 positive margins; pT3a negative margins; pT3a positive margins; pT3b; vs positive nodes) to predict biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer-specific mortality. RESULTS: Median follow up was 8.7 years, during which, 937 (34%) had biochemical recurrence, 108 (4%) castration-resistant prostate cancer, 127 (5%) metastases and 68 (2%) prostate cancer-specific mortality. For the outcomes of biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer-specific mortality, the c-indices were, respectively: prostate-specific antigen 0.65, 0.66, 0.64 and 0.69; Gleason score 0.66, 0.83, 0.76 and 0.85; and pathological stage group 0.69, 0.76, 0.72 and 0.80. CONCLUSIONS: Gleason score can predict with very high accuracy prostate cancer-specific mortality in patients undergoing radical prostatectomy. Thus, Gleason score should be given more weight in nomograms to predict prostate cancer-specific mortality. Furthermore, men with a high Gleason score should be given special consideration for adjuvant treatment or referral to clinical trials because of a higher risk of prostate cancer-specific mortality.
-
Does quality of radiation therapy predict outcomes of multicenter cooperative group trials? A literature reviewFairchild, Alysa; Straube, William; Laurie, Fran; Followill, David S. (2013-10-01)Central review of radiation therapy (RT) delivery within multicenter clinical trials was initiated in the early 1970s in the United States. Early quality assurance publications often focused on metrics related to process, logistics, and timing. Our objective was to review the available evidence supporting correlation of RT quality with clinical outcomes within cooperative group trials. A MEDLINE search was performed to identify multicenter studies that described central subjective assessment of RT protocol compliance (quality). Data abstracted included method of central review, definition of deviations, and clinical outcomes. Seventeen multicenter studies (1980-2012) were identified, plus one Patterns of Care Study. Disease sites were hematologic, head and neck, lung, breast, and pancreas. Between 0 and 97% of treatment plans received an overall grade of acceptable. In 7 trials, failure rates were significantly higher after inadequate versus adequate RT. Five of 9 and 2 of 5 trials reported significantly worse overall and progression-free survival after poor-quality RT, respectively. One reported a significant correlation, and 2 reported nonsignificant trends toward increased toxicity with noncompliant RT. Although more data are required, protocol-compliant RT may decrease failure rates and increase overall survival and likely contributes to the ability of collected data to answer the central trial question.
-
The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803Spalding, Aaron C.; Hawkins, Douglas S.; Donaldson, Sarah S.; Anderson, James R.; Lyden, Elizabeth R.; Laurie, Fran; Wolden, Suzanne; Arndt, Carola; Michalski, Jeff M. (2013-11-01)PURPOSE: Radiation therapy remains an essential treatment for patients with parameningeal rhabdomyosarcoma (PMRMS), and early radiation therapy may improve local control for patients with intracranial extension (ICE). METHODS AND MATERIALS: To address the role of radiation therapy timing in PMRMS in the current era, we reviewed the outcome from 2 recent clinical trials for intermediate-risk RMS: Intergroup Rhabdomyosarcoma Study (IRS)-IV and Children's Oncology Group (COG) D9803. The PMRMS patients on IRS-IV with any high-risk features (cranial nerve palsy [CNP], cranial base bony erosion [CBBE], or ICE) were treated immediately at day 0, and PMRMS patients without any of these 3 features received week 6-9 radiation therapy. The D9803 PMRMS patients with ICE received day 0 X-Ray Therapy (XRT) as well; however, those with either CNP or CBBE had XRT at week 12. RESULTS: Compared with the 198 PMRMS patients from IRS-IV, the 192 PMRMS patients from D9803 had no difference (P < .05) in 5-year local failure (19% vs 19%), failure-free-survival (70% vs 67%), or overall survival (75% vs 73%) in aggregate. The 5-year local failure rates by subset did not differ when patients were classified as having no risk features (None, 15% vs 19%, P = .25), cranial nerve palsy/cranial base of skull erosion (CNP/CBBE, 15% vs 28%, P = .22), or intracranial extension (ICE, 21% vs 15%, P = .27). The D9083 patients were more likely to have received initial staging by magnetic resonance imaging (71% vs 53%). CONCLUSIONS: These data support that a delay in radiation therapy for high-risk PMRMS features of CNP/CBBE does not compromise clinical outcomes.