Down-regulation of MSH3 and MSH6 genes in female breast cancer patients receiving taxane-based therapy

Abstract

Abstract Background The DNA in each cell in our body is constantly in danger of becoming damaged. Most DNA damage gets repaired straight away via many different proteins encoded by DNA—repair genes. MSH3 and MSH6 are pivotal DNA repair genes maintaining human genome integrity. Dysregulated expression of such genes has its implications resulting in developing of adverse reactions in cancer breast patients receiving taxanes. Cancer chemotherapy with some of taxane class of agents are associated with significant neurotoxicity, arthralgias and myalgias that may offset the therapeutic benefits of taxane use. Our aim is to identify gene expression pattern of MSH3 and MSH6 DNA mismatch repair genes in female breast cancer patients who develop adverse reactions to taxane-based therapy. One hundred and five patients with histologically proven breast cancer who received paclitaxel (PTX) as a single agent or combination therapy have been enrolled along with a group of 50 females with benign breast lesions serving as controls.Gene expression studies of mismatch repair genes (MMR) genes; MSH3 and MSH6; have been performed by real-time PCR. Patients were divided into groups according to the determined type/grade of PTX-based toxicity and fold changes of both genes were estimated. Results In the present work both MMR genes showed significantly lower expression in all the studied patients compared to benign cases as a control group. Toxicity findings were encountered in 75.2% of the studied patient cohort. The most common observed type of toxicity was peripheral neuropathy (PN), 58.1% of the studied patients. Both MSH3 and MSH6 genes were significantly down-regulated in the presence of high grade PN toxicity ≥ 2 (p = 0.034 and 0.01); diarrhea toxicity (p = 0.02 and 0.008); dyspnea (p = 0.01 and 0.016) respectively and bone pain (p = 0.024 for MSH6 only). Conclusion Dysregulated expression of MMR GENES [MSH3and MSH6] can be implicated in paclitaxel—induced toxicity experienced by some cancer breast patients.

Keywords

• Mismatch repair genes
• Breast cancer
• Taxane-based therapy
• Toxicity prediction