Transcriptomic Analysis of Breast Cancer Patients Sensitive and Resistant to Chemotherapy: Looking for Overall Survival and Drug Resistance Biomarkers

Abstract

Worldwide breast cancer ranks first in mortality and incidence rates in women over 20 years old. Rather than one disease, breast cancer is a heterogeneous group of diseases that express distinct molecular profiles. Neoadjuvant chemotherapy is an important therapeutic strategy for breast cancer patients independently of their molecular subtype, with the drawback of resistance development. In addition, chemotherapy has adverse effects that combined with resistance could contribute to lower overall survival. Although great efforts have been made to find diagnostic and prognostic biomarkers for breast cancer and for response to targeted and immune therapy for this pathology, little has been explored regarding biomarkers of response to anthracyclines and taxanes based neoadjuvant chemotherapy. This work aimed to evaluate the molecular profile of patients who received neoadjuvant chemotherapy to identify differentially expressed genes (DEGs) that could be used as biomarkers of chemotherapy response and overall survival. Breast cancer patients who were candidates for neoadjuvant chemotherapy were enrolled in this study. After treatment and according to their pathological response, they were assigned as sensitive or resistant. To evaluate DEGs, Gene Ontology, Kyoto Encyclopedia Gene and Genome (KEGG), and protein–protein interactions, RNA-seq information from all patients was obtained by next-generation sequencing. A total of 1985 DEGs were found, and KEGG analysis indicated a great number of DEGs in metabolic pathways, pathways in cancer, cytokine–cytokine receptor interactions, and neuroactive ligand-receptor interactions. A selection of 73 DEGs was used further for an analysis of overall survival using the METABRIC study and the ductal carcinoma dataset of The Cancer Genome Atlas (TCGA) database. Nine DEGs correlated with overall survival, of which the subexpression of C1QTNF3, CTF1, OLFML3, PLA2R1, PODN, KRT15, HLA-A, and the overexpression of TUBB and TCP1 were found in resistant patients and related to patients with lower overall survival.

Upregulated keratin 15 links to the occurrence of lymphovascular invasion, stromal cervical invasion as well as unfavorable survival profile in endometrial cancer patients

“…[ 12 ] Besides, another study reveals that KRT15 overexpression is associated with tumor metastasis in breast cancer patients. [ 17 ] In the present study, KRT15 protein expression was correlated with the occurrence of lymphovascular invasion and more advanced FIGO stage; meanwhile, KRT15 mRNA expression was correlated with the more advanced FIGO stage and marginally associated with the occurrence of stromal cervical invasion. Possible explanations could be that: KRT15 upregulation is associated with enhanced cancer stem cell property which exhibits a strong infiltration capacity; thus, KRT15 overexpression is linked with the occurrence of lymphovascular invasion and stromal cervical invasion in EC patients.…”

“…[ 12 ] Differently, it is illustrated that KRT15 is downregulated in carcinoma tissue compared with normal tissue from breast cancer patients. [ 14 , 15 , 17 ] KRT15 expression discloses an opposite trend in breast cancer, which might be explained by that: The apoptosis and differentiation of KRT15 would be influenced by endocrine status, hence, we hypothesize that KRT15 expression in breast cancer might be affected by the hormonal environment (such as estrogen, progesterone, etc) [ 18 , 19 ] ; whereas, this speculation needs further investigation in the in vivo and in vitro studies. In the current study, it was discovered that KRT15 was higher in tumor tissue compared with adjacent tissue; meanwhile, it exhibited an acceptable capability in distinguishing tumor tissue from adjacent tissue.…”

“…[23,24] Apart from the above-mentioned relevance of KRT15 with clinical features, its upregulation also links with an unsatisfying survival profile in breast cancer and non-small cell lung cancer. [17,25] Herein, the KRT15 overexpression was marginally correlated with accumulating DFS and OS in EC patients, which was estimated by Kaplan-Meier method and analyzed by log-rank test, whereas further adjusted multivariate Cox's regressions showed that tumor KRT15 protein (high vs low) was independently correlated with poor DFS and OS. Possible explanations could be that KRT15 overexpression is linked with enhanced cancer stem cell properties and therefore lined with a higher recurrence rate; thus, KRT15 overexpression is correlated with poor survival indexes.…”

Identifying Hub Genes Associated with Neoadjuvant Chemotherapy Resistance in Breast Cancer and Potential Drug Repurposing for the Development of Precision Medicine

“…RNA-Seq data samples of breast cancer patients sensitive and resistant to neoadjuvant chemotherapy were downloaded from the GEO database, GSE162187 [ 114 ] and GSE163882 [ 115 ]. A total of 89 data samples sensitive to treatment and 154 data samples resistant to the treatment were used for downstream analysis.…”

Bioinformatics Identification of TUBB as Potential Prognostic Biomarker for Worse Prognosis in ERα-Positive and Better Prognosis in ERα-Negative Breast Cancer

“…It has been indicated that TUBB mediates cell cycle, epithelial-mesenchymal transition (EMT), proliferation, metastasis, and invasion in cutaneous melanoma, possibly through the downregulation of tumor suppressor miR-339-3p [ 14 ]. It has been shown recently that TUBB mRNA expression is upregulated in breast cancer patients resistant to chemotherapy [ 10 , 15 ]. Mutations in TUBB have been shown to demonstrate resistance to chemotherapy [ 16 , 17 ], in which the l240I mutation shows specific resistance to vincristine [ 18 ].…”