Whole Genome Transcriptome Analysis of the Association between Obesity and Triple-Negative Breast Cancer in Caucasian Women

Abstract

Background: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this exploratory study was to investigate the association between obesity and TNBC in premenopausal and postmenopausal Caucasian women using transcription profiling. Methods: We compared gene expression levels of tumor samples drawn from normal weight, overweight, and obese pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. Results: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight, and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways associating obesity with TNBC. The discovered pathways included the unfolded protein response, endoplasmic reticulum stress, B cell receptor, and autophagy signaling pathways in obese premenopausal women; and the integrin, axonal guidance, ERK/MAPK (extracellular-signal-regulated kinase/mitogen activated protein kinase) and glutathione biosynthesis signaling pathways in obese postmenopausal women. Conclusions: The results suggest that both overweight and obese status are associated with TNBC, highlighting the need for conformation of these results in independent studies.

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

“…Even if a recent genomic analysis revealed molecular networks and biological pathways associating obesity with TNBC [38], a recent meta-analysis with 4412 TNBC patients showed no significant association between obesity and DFS (p ¼ 0.60) or OS (p ¼ 0.71) [39]. In our analysis, the sample size of hormone receptor-negative subgroup was underpowered to allow any subgroup analysis difference (only 11% of total population).…”

Integration of Transcriptome and Metabolome Provides Unique Insights to Pathways Associated With Obese Breast Cancer Patients

“…Furthermore, other studies have performed the integration between transcriptomic and metabolomic data (14,(56)(57)(58). Interestingly, the molecular mechanisms underlying the association between obesity and BC risk are not well-understood and still unclear (18). In an effort to reduce the knowledge gap, we performed these experiments to clarify the potential relationship between obesity and BC by the integration of the peripheral blood differential transcriptomic and metabolomic profiles at the pathway level.…”

“…Recently, omics techniques, such as transcriptomics and metabolomics, have been widely used to improve understanding of the underlying biological mechanisms and biomarkers identification (14). Many studies utilized transcriptomics to investigate human diseases at the molecular level and identify the variation in transcriptomic profile in relation to diagnostic, treatment, or management and that may help to understand the mechanisms of disease initiation and progression (15)(16)(17)(18)(19). Moreover, many transcriptomic studies have been based on the analysis of the association between BC and obesity (18,20).…”

“…Many studies utilized transcriptomics to investigate human diseases at the molecular level and identify the variation in transcriptomic profile in relation to diagnostic, treatment, or management and that may help to understand the mechanisms of disease initiation and progression (15)(16)(17)(18)(19). Moreover, many transcriptomic studies have been based on the analysis of the association between BC and obesity (18,20). On the other hand, metabolomic investigations have been widely utilized in cancer metabolism and biomarkers identification to deduce the onset and progression of cancer (21,22).…”

Risk Factors for Triple-Negative Breast Cancer among Latina Women

“…On the other hand, obesity in postmenopausal women could act as a risk factor, mainly attributed to a higher expression of genes related to inflammation. It has been recently described that the ERK/MAPK signaling pathway is associated with TN breast cancer in obese postmenopausal women; upstream regulators of this pathway include TNF, TGFb1, and IL1 (59,60). Additionally, high levels of insulin and insulin-like growth factors (61), along with glucose levels, cytokines, adipokines, and chronic inflammation, might be associated with the increased risk for ER-negative subtypes (55,62,63); nevertheless, these findings have been found mainly in studies conducted in NHW women (54).…”