Genetics and Expression Profile of the Tubulin Gene Superfamily in Breast Cancer Subtypes and Its Relation to Taxane Resistance

Abstract

Taxanes are a class of chemotherapeutic agents that inhibit cell division by disrupting the mitotic spindle through the stabilization of microtubules. Most breast cancer (BC) tumors show resistance against taxanes partially due to alterations in tubulin genes. In this project we investigated tubulin isoforms in BC to explore any correlation between tubulin alterations and taxane resistance. Genetic alteration and expression profiling of 28 tubulin isoforms in 6714 BC tumor samples from 4205 BC cases were analyzed. Protein-protein, drug-protein and alterations neighbor genes in tubulin pathways were examined in the tumor samples. To study correlation between promoter activity and expression of the tubulin isoforms in BC, we analyzed the ChIP-seq enrichment of active promoter histone mark H3K4me3 and mRNA expression profile of MCF-7, ZR-75-30, SKBR-3 and MDA-MB-231 cell lines. Potential correlation between tubulin alterations and taxane resistance, were investigated by studying the expression profile of taxane-sensitive and resistant BC tumors also the MDA-MB-231 cells acquired resistance to paclitaxel. All genomic data were obtained from public databases. Results showed that TUBD1 and TUBB3 were the most frequently amplified and deleted tubulin genes in the BC tumors respectively. The interaction analysis showed physical interactions of α-, β- and γ-tubulin isoforms with each other. The most of FDA-approved tubulin inhibitor drugs including taxanes target only β-tubulins. The analysis also revealed sex tubulin-interacting neighbor proteins including ENCCT3, NEK2, PFDN2, PTP4A3, SDCCAG8 and TBCE which were altered in at least 20% of the tumors. Three of them are tubulin-specific chaperons responsible for tubulin protein folding. Expression of tubulin genes in BC cell lines were correlated with H3K4me3 enrichment on their promoter chromatin. Analyzing expression profile of BC tumors and tumor-adjacent normal breast tissues showed upregulation of TUBA1A, TUBA1C, TUBB and TUBB3 and downregulation of TUBB2A, TUBB2B, TUBB6, TUBB7P pseudogene, and TUBGCP2 in the tumor tissues compared to the normal breast tissues. Analyzing taxane-sensitive versus taxane-resistant tumors revealed that expression of TUBB3 and TUBB6 was significantly downregulated in the taxane-resistant tumors. Our results suggest that downregulation of tumor βIII- and βV-tubulins is correlated with taxane resistance in BC. Based on our results, we conclude that aberrant protein folding of tubulins due to mutation and/or dysfunction of tubulin-specific chaperons may be potential mechanisms of taxane resistance. Thus, we propose studying the molecular pathology of tubulin mutations and folding in BC and their impacts on taxane resistance.

Four-weekly Low-dose Gemcitabine and Paclitaxel in Patients With Platinum-resistant Urothelial Cancer and Performance Status 2/3

“…We have reported that HuR and TUBB3 are useful predictors of outcome with regard to gemcitabine-and paclitaxel-based regimens in patients with UC (13,17). Similar findings were also reported in other types of cancer (21)(22)(23). However, the present study showed that neither of these markers was individually significantly associated with OS.…”

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti‐HER2 therapy using transcriptomic data of 3,104 breast cancer patients

“…Taxenes disrupt microtubule function and genes involved in microtubule setup and assembly, including TUBB1, TUBB4, microtubule‐associated protein 2 (MAP2) and microtubule‐associated protein 4 (MAP4), therefore have a critical role in resistance. TUBB1 was recently described as the gene with the most frequently altered and amplified isoforms in breast cancer . TUBB4 had higher expression in an MCF7 cell line engineered to withstand paclitaxel treatment by administering gradually increasing concentrations of the drug .…”

Upregulated Expression of TUBA1C Predicts Poor Prognosis and Promotes Oncogenesis in Pancreatic Ductal Adenocarcinoma via Regulating the Cell Cycle

“…Some researches indicated that TUBA1C was implicated in cell proliferation and cell cycle in numerous cancers (26,27). Meanwhile, previous studies demonstrated TUBA1C upregulation could significantly impact tumor growth and progression (28,29). In addition, it was reported that TUBA1C has emerged as a critical intermediary in the cell cycle signaling pathway (21).…”