Abstract
BackgroundDistant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients’ life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor.Methods/FindingsTo identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response), established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test). Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method).ConclusionsThese data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer.
Highlights
The searching for predictive tumor biomarkers in breast cancer treatment has been a major research issue for decades [1,2]
These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer
After comparing pre-chemotherapy and post-chemotherapy samples, we identified a subset of 65 gene sequences whose expression was significantly up-regulated after chemotherapy considering all groups (Figure 1A, 1B, Table S1)
Summary
The searching for predictive tumor biomarkers in breast cancer treatment has been a major research issue for decades [1,2]. Despite substantial advances in this field, around 30% of patients with early-stage breast cancer relapse after an unpredictable period, even if they achieved a good response to systemic treatment [3,5] This and other scientific findings, such as the detection of circulating tumor cells (CTCs) in the bloodstream of treated patients, has pointed out tumor chemoresistance as a leading process involved in breast cancer progression [10,11]. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor
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