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PAKT pathway activation is associated with PIK3CA mutations and good prognosis in luminal breast cancer in contrast to p-mTOR pathway activation.

ABSTRACT: Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. We developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Our analysis revealed that the pAKT pathway activation was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p?

SUBMITTER: Sonnenblick A

PROVIDER: S-EPMC6355773 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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pAKT pathway activation is associated with <i>PIK3CA</i> mutations and good prognosis in luminal breast cancer in contrast to p-mTOR pathway activation.

Sonnenblick Amir A Venet David D Brohée Sylvain S Pondé Noam N Sotiriou Christos C

NPJ breast cancer 20190131

Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. We developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Our analysis revealed that the pAKT pathway activation was associat ...[more]

PMID: 30729154

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Dissecting the AKT/mTOR pathway in estrogen receptor positive breast cancers identifies phosphorylated AKT to be associated with luminal A, PIK3CA mutations and good prognosis in contrast to phosphorylated mTOR

Project description:This SuperSeries is composed of the SubSeries listed below.

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Increased MAPK1/3 Phosphorylation in Luminal Breast Cancer Related with PIK3CA Hotspot Mutations and Prognosis.

Project description:IntroductionWhile mutations in PIK3CA are most frequently (45%) detected in luminal breast cancer, downstream PI3K/AKT/mTOR pathway activation is predominantly observed in the basal subtype. The aim was to identify proteins activated in PIK3CA mutated luminal breast cancer and the clinical relevance of such a protein in breast cancer patients.Materials and methodsExpression levels of 171 signaling pathway (phospho-)proteins established by The Cancer Genome Atlas (TCGA) using reverse phase protein arrays (RPPA) were in silico examined in 361 breast cancers for their relation with PIK3CA status. MAPK1/3 phosphorylation was evaluated with immunohistochemistry on tissue microarrays (TMA) containing 721 primary breast cancer core biopsies to explore the relationship with metastasis-free survival.ResultsIn silico analyses revealed increased phosphorylation of MAPK1/3, p38 and YAP, and decreased expression of p70S6K and 4E-BP1 in PIK3CA mutated compared to wild-type luminal breast cancer. Augmented MAPK1/3 phosphorylation was most significant, i.e. in luminal A for both PIK3CA exon 9 and 20 mutations and in luminal B for exon 9 mutations. In 290 adjuvant systemic therapy naïve lymph node negative (LNN) breast cancer patients with luminal cancer, high MAPK phosphorylation in nuclei (HR=0.49; 95% CI, 0.25-0.95; P=.036) and in tumor cells (HR=0.37; 95% CI, 0.18-0.79; P=.010) was related with favorable metastasis-free survival in multivariate analyses including traditional prognostic factors.ConclusionEnhanced MAPK1/3 phosphorylation in luminal breast cancer is related to PIK3CA exon-specific mutations and correlated with favorable prognosis especially when located in the nuclei of tumor cells.

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Project description:Dissecting the AKT/mTOR pathway in estrogen receptor positive breast cancers identifies phosphorylated AKT to be associated with luminal A, PIK3CA mutations and good prognosis in contrast to phosphorylated mTOR

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PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors.

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PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system.

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