Abstract
In breast cancer, it is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma in situ (DCIS) to basal-like tumors. By applying weighted gene co-expression network analysis (WGCNA), we identified 17 gene co-expression modules in normal, DCIS and basal-like tumor samples. We then correlated the expression pattern of these gene modules with disease progression from normal to basal-like tumours and found eight modules exhibiting a high and statistically significant correlation. M4 included genes mainly related to cell cycle/division and DNA replication like CCNA2 or CDK1. The M7 module included genes linked with the immune response showing top hub genes such as CD86 or PTPRC. M10 was found specifically correlated to DCIS, but not to basal-like tumor samples, and showed enrichment in ubiquitination or ubiquitin-like processes. We observed that genes in some of these modules were associated with clinical outcome and/or represented druggable opportunities, including AURKA, AURKB, PLK1, MCM2, CDK1, YWHAE, HSP90AB1, LCK, or those targeting ubiquitination. In conclusion, we describe relevant gene modules related to biological functions that can influence survival and be targeted pharmacologically.
Highlights
Cancer is an evolutionary disease where the accumulation of genetic alterations leads epithelial cells to transform to premalignant lesions that may evolve to tumor cells [1, 2].Accumulation of molecular alterations over time produces a gain of different biological functions that permits cells to proliferate, avoid programmed death, migrate or seed in distant tissue [3]
It is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma in situ (DCIS) to basal-like tumors
Overall these analyses indicate that the major factor structuring transcriptomic variance among these samples correspond to disease
Summary
Accumulation of molecular alterations over time produces a gain of different biological functions that permits cells to proliferate, avoid programmed death, migrate or seed in distant tissue [3]. Cells that seed and proliferate in distant organs form metastases that compromise patient life. Among these functions, deregulation of cell division and genomic instability are key characteristics of transformed cells and several therapies aiming to inhibit these functions have reached the clinical setting [4]. The acquisition of the mentioned deregulated functions is produced at different time points in the evolution of cancer, so the identification of druggable options against these alterations could undoubtedly open avenues for the design of novel therapies
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