Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer

Heinonen, Henna; Nieminen, Anni I.; Saarela, Matti; Kallioniemi, Anne; Klefström, Juha; Hautaniemi, Sampsa; Monni, Outi

doi:10.1186/1471-2164-9-348

Cited by 76 publications

(53 citation statements)

References 41 publications

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“…On the other hand, subtype A had significant downregulation of the activating thr-412 phosphorylation on p70S6K, the exact opposite effect seen in the subtype B (Table 6). That cases in both subtypes are highly correlated with the disease suggests that p70S6K dysregulation may have less to do with the pathogenesis of the disease and perhaps more to do with the different correlation structure observed between the two subtypes since p70S6K plays an important role in regulating both translation and transcription (12).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Stamper

Mecham

Park

et al. 2012

Physiological Genomics

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. Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation. Physiol Genomics 44: 1154-1163. First published October 16, 2012 doi:10.1152/physiolgenomics.00085.2012The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. To identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML. Am J Med Genet A 155A: 91-97, 2011). Elevated IRS1 (pan-tyr) and GSK3␤ (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3␤ (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412), and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.

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Section: Discussionmentioning

confidence: 99%

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Stamper

Mecham

Park

et al. 2012

Physiological Genomics

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“…Heinonen et al [13] have reported that p70S6K is over-expressed in primary breast cancer tissues, and its upregulation is associated with aggressive disease and poor prognosis of patients with breast cancer. Moreover, p70S6K also has a crucial role in cell growth by regulating cell size and progression of cell cycle [14]. However, the roles of mTOR/p70S6K signal transduction pathway in osteosarcoma, which is one of the most rapidly growing sarcomas, remain unknown.…”

Section: Introductionmentioning

confidence: 99%

mTOR/p70S6K Signal transduction pathway contributes to osteosarcoma progression and patients’ prognosis

et al. 2009

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The mTOR/p70S6K signal transduction pathway plays a key role in the regulation of cancer cells' survival and proliferation. However, its roles in osteosarcoma, which is one of the most rapidly growing sarcomas, remain unknown. This study investigated for the first time the correlation between the mTOR/p70S6K signal transduction pathway in human osteosarcoma and patients' prognosis. The expression patterns of mTOR and p70S6K in paraffin-embedded specimens gathered from 65 patients with primary osteosarcoma were detected by the method of immunohistochemistry using antibodies against mTOR and p70S6K. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Immunostaining revealed that the mTOR/p70S6K signal transduction pathway is activated in human osteosarcoma. Additionally, positive expression of mTOR and p70S6K proteins was significantly correlated with surgical stage, metastasis pattern and percentage of dead cells of osteosarcoma. Moreover, in univariate analysis, surgical stage, metastasis pattern and percentage of dead cells, mTOR and p70S6K expression showed significant influence on overall survival (OS) and disease-free survival (DFS). In multivariate analysis, surgical stage (IIA vs. IIB/III), metastasis pattern (without vs. with), percentage of dead cells (≥90 vs. <90%), mTOR expression pattern (negative vs. positive) and p70S6K expression pattern (negative vs. positive) were significant for DFS and OS. Our results demonstrate the correlation of mTOR and p70S6K expression patterns with the oncological progression of osteosarcoma patients, suggesting the prognostic significance of the mTOR/p70S6K signal transduction pathway in osteosarcoma patients, which may lay a foundation for making further investigations on the mTOR/p70S6K signal transduction pathway as a potential target for osteosarcoma therapy.

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“…Heinonen et al has determined p70S6K and PI3K/mTOR/p70S6K pathway dependent gene expression profiles by micro-arrays using five breast cancer cell lines with predefined gene copy number and gene expression alterations. He suggested that p70S6K over-expression is associated with aggressive disease and poor prognosis of breast cancer patients; the potential downstream targets of p70S6K and the whole PI3K/mTOR/p70S6K pathway identified, may have diagnostic value [56].…”

Section: Journal Of Surgical Oncologymentioning

confidence: 99%

Genomic profiling of breast cancer

Pandey

Singh

Maurya

et al. 2009

Journal of Surgical Oncology

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Genome study provides significant changes in the advancement of molecular diagnosis and treatment in Breast cancer. Several recent critical advances and high-throughput techniques identified the genomic trouble and dramatically accelerated the pace of research in preventing and curing this malignancy. Tumor-suppressor genes, Proto-oncogenes, DNA-repair genes, Carcinogen-metabolism genes are critically involved in progression of breast cancer. We reviewed imperative finding in breast genetics, ongoing work to segregate further susceptible genes, and preliminary studies on molecular profiling.

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Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer

Cited by 76 publications

References 41 publications

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

mTOR/p70S6K Signal transduction pathway contributes to osteosarcoma progression and patients’ prognosis

Genomic profiling of breast cancer

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