Dysregulation of PI3K/Akt/PTEN Pathway in Canine Mammary Tumor

Abstract

The PI3K/Akt/PTEN axis is one of the most important signaling pathways in tumorigenesis. Recently, mutation of PIK3CA has been highlighted due to the similarities of mutational hotspots in both dogs and humans. PIK3CA H1047R (c.3140A > G) has been discovered as the most common mutational hot spot in canine mammary tumor in recent studies, while the feature of PIK3CA-mutated canine mammary tumor is obscure. Methods: A total of 83 mammary samples classified as normal (n = 13), adenoma (n = 25), low-grade carcinoma (n = 21), and high-grade carcinoma (n = 24) were included in this study. Genomic DNA from each sample was extracted, amplified by conventional PCR, and analyzed through Sanger sequencing. Analysis for the expression of PIK3CA, Akt, p-Akt, and PTEN was performed by immunohistochemistry, and of Akt2 by RNA in situ hybridization. Results: PIK3CA H1047R mutation was detected in 14.3% (10/70) of tumor samples. Dysregulation of p-Akt, Akt2, and PTEN was observed in mammary tumor samples, but only PTEN dysregulation was associated with PIK3CA H1047R mutation. Conclusions: The present study showed that dysregulation of components in the PI3K/Akt/PTEN pathway is a feature of canine mammary tumors, but this dysregulation is not directly correlated to the PIK3CA H1047R mutation except for PTEN expression.

Molecular Characterization of CF33 Canine Cell Line and Evaluation of Its Ability to Respond against Infective Stressors in Sight of Anticancer Approaches

“…The role of PTEN , one of the main tumor suppressor genes, in down-regulation or mutation/deletion in breast cancers has been shown in other studies [ 42 ]. Herein we report its non-continuous expression; other studies have shown that copy number aberrations of PTEN are associated with negative evolution of CMCs and HBC [ 42 , 43 ]. In the study by Asproni et al [ 44 ], the authors reported that reduction of PTEN immunohistochemical expression can lead to the interruption of the inhibition of the PI3K/AKT pathway, resulting in glycolysis activation for ATP production compared to mitochondrial respiration; therefore PTEN immunohistochemical expression is correlated with less aggressive tumors, no lymphatic invasion, and enhanced survival rates.…”

Review: The PI3K-AKT-mTOR signal transduction pathway in canine cancer

“…181 Similar pathway mutations have also been identified in canine mammary gland tumors (cMGTs), including recurrent somatic PIK3CA variants and PTEN deletions with loss of heterozygosity associated with poor prognosis. 8,22,131,132 There are also similarities in gene expression signatures, characterized by PI3K-AKT, PTEN, and MAPK pathway enrichment. 264 PI3K pathway alterations are reported in 50% of cMGT with the PIK3CA H1047R mutation affecting 26% of tumors examined.…”

“…5 However, continued research is required to elucidate the indirect correlation between mutation status and PI3K-AKT-mTOR pathway dysregulation in cMGT. 118,131 In an immunohistochemical study of cMGTs, greater PI3K immunoreactivity was significantly associated with regional lymph node infiltration, distant metastasis, ERBB2+ tumors, and the lowest survival rate. 208 The study found a positive correlation between PI3K immunoreactivity and triple-negative tumors compared with those with hormone receptor expression, as well as greater PI3K immunoreactivity in luminal B phenotype versus luminal A.…”

“…Total and/or pAKT, 4EBP1, and mTOR can be evaluated using immunohistochemistry, and has been reported for some tumor types. 11,52,131,219 Unfortunately, phosphoprotein epitopes are often difficult to detect by immunohistochemistry following decalcification of OSAs. In such cases, unphosphorylated targets may be used as indirect indicators of pathway activation, such as intracellular immunolocalization of FOXO1, as demonstrated in human neoplasms.…”

Homoharringtonine induces apoptosis of mammary carcinoma cells by inhibiting the AKT/mTOR signaling pathway

“…14 Thus, HHT may inhibit tumour growth in CMC. Kim et al found using Sanger sequencing that AKT and p-AKT are abnormally expressed in CMC, 15 which may be associated with cancer occurrence and development. Therefore, searching for small-molecule drugs that inhibit the AKT pathway has become a focus of attention.…”