Abstract
PurposeAlthough 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 resultsGene 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.ConclusionIn 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.
Highlights
Breast cancer is the leading cause of cancer-related death among women worldwide [1]
We performed gene expression analyses in a cohort of 269 breast cancer patients based on their body mass index (BMI)
We describe biological functions and protein–protein interaction (PPI) networks associated with obesity in luminal A tumors, which we found generally associated with worse outcome in luminal A patients
Summary
Breast cancer is the leading cause of cancer-related death among women worldwide [1]. 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]. As an example, increased presence of insulin or insulinlike growth factors can affect tumor growth and response to treatment [9] In this context, breast tumors that express estrogen receptors are more dependent on stimulating factors [10]
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