Analysis of genes involved in the PI3K/Akt pathway in radiation- and MNU-induced rat mammary carcinomas

Abstract

The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells. The negative pathway regulator Inpp4b was significantly downregulated in both groups, compared with in normal mammary tissue, and radiation-induced carcinomas also showed a significant decrease in Pten expression, while the chemically induced carcinomas showed a decrease in Pik3r1 and Pdk1. Significant upregulation of the positive regulators Erbb2 and Pik3ca was observed only in chemically induced carcinomas. However, no genes showed clear correlations with AKT phosphorylation levels, except in individual carcinomas. Only rare carcinomas showed mutations in PI3K/AKT pathway genes, yet these carcinomas did not exhibit stronger AKT phosphorylation. Thus, while AKT phosphorylation is a common feature of rat mammary carcinomas induced by radiation or a canonical chemical carcinogen, the mutation of key genes in the pathways or permanent changes to gene expression of particular signaling proteins do not explain the pathway activation in the advanced cancers. Although AKT signaling likely facilitates cancer development and growth in rat mammary carcinomas, it is unlikely that permanent disruption of the PI3K/AKT pathway genes is a major causal event in radiation carcinogenesis.

Neutron-induced Rat Mammary Carcinomas Are Mainly of Luminal Subtype and Have Multiple Copy Number Aberrations

“…Moreover, various animal experiments have revealed that neutrons have a strong effect on mammary carcinogenesis (8). Other studies have revealed various genomic and epigenomic alterations in radiation-induced cancers (9,10). Although copy number aberrations are common in many types of tumors, there are only a few findings on genetic alterations of cancers induced by neutrons (11).…”

Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas

“…retained for further study; immunotyping indicated that the majority of the carcinomas were of the luminal subtype. 30…”

“…27 Female Sprague-Dawley (SD) rats are highly susceptible to mammary carcinogenesis. 30 For the study reported herein, to identify genes with potential changes in functionally relevant DNA methylations related to radiation-induced mammary carcinomas, we conducted genome-wide analyses of the changes in DNA methylation and gene expression in rat mammary carcinomas induced by radiation exposure using the F1 hybrid SD-COP model. 29 However, no obvious candidate signaling pathway was found based on the relationships between the hypermethylated and differentially expressed genes in the radiation-induced mammary carcinomas.…”

“…In our recent study using F1 hybrid of SD rats and mammary cancer-resistant Copenhagen (COP) rats, abnormal expression of genes involved in the PI3K/Akt pathway, a frequently dysregulated pathway in human breast cancer, was observed in radiation-induced rat mammary carcinomas, although the number of cancer-related mutations was small, suggesting the involvement of epigenetic alterations. 30 For the study reported herein, to identify genes with potential changes in functionally relevant DNA methylations related to radiation-induced mammary carcinomas, we conducted genome-wide analyses of the changes in DNA methylation and gene expression in rat mammary carcinomas induced by radiation exposure using the F1 hybrid SD-COP model. Our study indicated that polycomb repressive complex 2 (PRC2)-mediated DNA methylation of developmentally related transcription-factor genes is critical for dysregulation of developmentally related genes in radiationinduced mammary carcinogenesis.…”

Deletion of Cdkn1b in ACI rats leads to increased proliferation and pregnancy-associated changes in the mammary gland due to perturbed systemic endocrine environment

“…Most of these studies have been conducted in rats using chemical carcinogens (i.e., 7,12-dimethyl-benz[a]anthracene or N-methyl-N-nitrosourea) to induce mammary cancer [9]. Carcinogen-induced mammary tumors in rats are ovarian-hormone dependent (70% ER + ; 30% ER - ), but these carcinogens are not implicated in human breast cancer although several of the mutations initiated by them, such as those in PIK3CA , are also commonly observed in human breast tumors [10, 11]. A rodent model of breast cancer that closely resembles the genotype and phenotype of estrogen-dependent human breast tumors involves estrogen (i.e.…”