Functional transcriptomic annotation and protein–protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer
Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer
Miriam Nuncia‑Cantarero 0 1 2
Sandra Martinez‑Canales 0 1 2
Fernando Andrés‑Pretel 0 1 2
Gabriel Santpere 0 1 2
Alberto Ocaña 0 1 2
Eva Maria Galan‑Moya 0 1 2
Eva Maria Galan-Moya 0 1 2
0 Department of Neuroscience, Yale School of Medicine , New Haven, CT , USA
1 Translational Research Unit, University Hospital , Albacete , Spain
2 Translational Oncology Laboratory, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha (UCLM) , C/Almansa 14, 02008 Albacete , Spain
Purpose Although obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients. Methods and results Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome. Conclusion In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.
Breast cancer; Transcriptomic analysis; Protein-protein interaction; Clinical outcome; Novel druggable targets; Targeted therapy
Introduction
Breast cancer is the leading cause of cancer-related death
among women worldwide [
1
]. To this regard, several factors
are involved in the initiation and promotion of breast tumors
including molecular alterations at the genomic level such as
mutations or copy number alterations [
2, 3
]. Indeed, using
functional studies, some of these genomic modifications
have been clearly associated with a malignant phenotype,
contributing to the oncogenesis of epithelial cells [
4, 5
]. In
addition to these molecular alterations, cancer cells rely on
the surrounding microenvironment, where non-transformed
cells and stromal components facilitate tumor growth by
the secretion of autocrine signals like growth factors [
6
].
Stimulation of cancer cells by paracrine-secreted factors
from interstitial cells including fibroblasts, neutrophils, or
endothelial cells can stimulate functions such as
proliferation, survival, or migration, which are necessary to the tumor
formation and dissemination [
7, 8
]. However, components of
the tumor stroma depend on different conditions and can
differ among individuals. Of note, adipose tissue is one of the
main components of the breast cancer microenvironment,
and therefore, accumulation of fat tissue in the stroma can
modify settings of tumor cells and influence their survival
[8]. As an example, increased presence of insulin or
insulinlike growth factors can affect tumor growth but also response
to treatment [
9
]. In this context, breast tumors that express
estrogen receptors are more dependent on stimulating
factors [
10
].
Besides being a risk factor for cancer, obesity has also
been associated with detrimental patient outcome, especially
in postmenopausal patients [
5, 4
]. A number of
epidemiological studies have demonstrated that how obesity is directly
related to cancer mortality. In this sense, an increased body
mass index (BMI) has been strongly linked with poor
survival in postmenopausic patients carrying estrogen
receptor positive tumors [11]. One of the mechanisms proposed
to explain how obesity increases breast cancer risk is that
adipocyte-secreted hormones could be promoting tumor
progression through an increase of cellular proliferation [
12
].
However, little effort has been put into clarifying how the
excess of adipose tissue in the tumor niche influences the
molecular characteristics of the res (...truncated)