Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma

Shull, Austin Y.; Latham-Schwark, Alicia; Ramasamy, Poornema; Leskoske, Kristin L.; Oroian, Dora; Birtwistle, Marc R.; Buckhaults, Phillip

doi:10.1371/journal.pone.0043369

Cited by 79 publications

(72 citation statements)

References 38 publications

(48 reference statements)

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“…This gene serves a role in cell growth, differentiation, proliferation, motility, survival and intracellular transport, and its route is associated with the progression of melanoma (37,38). The PIK3R5 gene is associated with inhibition of autophagy (promoting tumor growth) (39) and certain authors have suggested that autophagy also works as a cytoprotective mechanism (40).…”

Section: Discussionmentioning

confidence: 99%

Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma

Paula

Moraes²,

Canto³

et al. 2016

Oncology Letters

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Abstract. Nodal status is the most significant independent prognostic factor in breast cancer. Identification of molecular markers would allow stratification of patients who require surgical assessment of lymph nodes from the large numbers of patients for whom this surgical procedure is unnecessary, thus leading to a more accurate prognosis. However, up to now, the reported studies are preliminary and controversial, and although hundreds of markers have been assessed, few of them have been used in clinical practice for treatment or prognosis in breast cancer. The purpose of the present study was to determine whether protein phosphatase Mg2+/Mn2+ dependent 1D, β-1,3-N-acetylglucosaminyltransferase, neural precursor cell expressed, developmentally down-regulated 9, prohibitin, phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5), phosphatidylinositol-5-phosphate 4-kinase type IIα, TRF1-interacting ankyrin-related ADP-ribose polymerase 2, BCL2 associated agonist of cell death, G2 and S-phase expressed 1 and PAX interacting protein 1 genes, described as prognostic markers in breast cancer in a previous microarray study, are also predictors of lymph node involvement in breast carcinoma Reverse transcription-quantitative polymerase chain reaction analysis was performed on primary breast tumor tissues from women with negative lymph node involvement (n=27) compared with primary tumor tissues from women with positive lymph node involvement (n=23), and was also performed on primary tumors and paired lymph node metastases (n=11). For all genes analyzed, only the PIK3R5 gene exhibited differential expression in samples of primary tumors with positive lymph node involvement compared with primary tumors with negative lymph node involvement (P= 0.0347). These results demonstrate that the PIK3R5 gene may be considered predictive of lymph node involvement in breast carcinoma. Although the other genes evaluated in the present study have been previously characterized to be involved with the development of distant metastases, they did not have predictive potential.

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Section: Discussionmentioning

confidence: 99%

Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma

Paula

Moraes²,

Canto³

et al. 2016

Oncology Letters

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“…In melanomas, activation of the PI3K pathway can act in concert with the RAS/ RAF pathway to promote melanoma tumorigenesis and metastasis (14,40). The PI3K signaling pathway is often upregulated in melanoma (3) through activating mutations of the PIK3CA gene encoding the p110␣ catalytic subunit (13,41,45), by loss-of-function mutations in PTEN, which have been detected in 10 to 30% of melanomas (50), by epigenetic silencing of PTEN expression (57), and by activation of AKT3 (46). The ability of PI3K to regulate expression of Brn-2, a transcription factor that can downregulate MITF expression to promote an invasive phenotype in vitro and in vivo (2,4,19,42,48), fits nicely with a role for PI3K signaling in promoting highly aggressive melanomas in a BRAF, Pten Ϫ/Ϫ mouse melanoma model (14).…”

Section: Discussionmentioning

confidence: 99%

A Phosphatidylinositol 3-Kinase–Pax3 Axis Regulates Brn-2 Expression in Melanoma

Bonvin

Falletta

Shaw

et al. 2012

Molecular and Cellular Biology

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bDeregulation of transcription arising from mutations in key signaling pathways is a hallmark of cancer. In melanoma, the most aggressive and lethal form of skin cancer, the Brn-2 transcription factor (POU3F2) regulates proliferation and invasiveness and lies downstream from mitogen-activated protein kinase (MAPK) and Wnt/␤-catenin, two melanoma-associated signaling pathways. In vivo Brn-2 represses expression of the microphthalmia-associated transcription factor, MITF, to drive cells to a more stem cell-like and invasive phenotype. Given the key role of Brn-2 in regulating melanoma biology, understanding the signaling pathways that drive Brn-2 expression is an important issue. Here, we show that inhibition of phosphatidylinositol 3-kinase (PI3K) signaling reduces invasiveness of melanoma cells in culture and strongly inhibits Brn-2 expression. Pax3, a transcription factor regulating melanocyte lineage-specific genes, directly binds and regulates the Brn-2 promoter, and Pax3 expression is also decreased upon PI3K inhibition. Collectively, our results highlight a crucial role for PI3K in regulating Brn-2 and Pax3 expression, reveal a mechanism by which PI3K can regulate invasiveness, and imply that PI3K signaling is a key determinant of melanoma subpopulation diversity. Together with our previous work, the results presented here now place Brn-2 downstream of three melanoma-associated signaling pathways.

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“…A report that analyzed 68 metastatic melanomas showed that 41% presented a mutation in this pathway [102]. Besides 3% of metastatic melanomas presents activating mutation of PI3K and 5-20% of late-stage melanoma present mutations that leads to PTEN loss, which is the protein most commonly mutated in this pathway [1].…”

Section: Pi3kmentioning

confidence: 99%