Abstract
The Leucine Zipper Tumor Suppressor 1 (LZTS1) is a tumor suppressor gene, located at chromosome 8p22, which is frequently altered in human cancer. In normal tissue, its ubiquitous expression regulates cell mitosis by the stabilization of microtubule networks. LZTS1-deficient mouse embryonic fibroblasts have been shown to have an accelerated mitotic progression, and a higher resistance to taxanes, microtubule-stabilizing drugs. We investigate the role of Lzts1 in paclitaxel-resistance in breast cancer cells. Downregulation of Lzts1 expression significantly decreases sensitivity to paclitaxel in vitro. We further analyzed Lzts1 expression by immunohistochemistry in 270 primary breast cancer samples and 16 normal breast specimens. Lzts1 was significantly downregulated in breast cancer samples and its deregulation was associated with a higher incidence of tumor recurrence, and to a worse overall survival. Moreover, Lzts1-negative tumors were associated with unfavorable outcome after taxanes-based therapy. Thus our data suggest that Lzts1 deregulation is involved in breast cancer and its immunohistochemical evaluation may serve as a prognostic factor for breast cancer therapy.
Highlights
Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide [1]
We have previously demonstrated that the loss of Lzts1 in mouse embryonic fibroblasts (MEFs) corresponds to an accelerated mitotic progression, and a higher resistance to paclitaxel-induced M phase arrest [24]
Taxanes have been successfully introduced in the polychemotherapy regiments for breast cancer treatment, conferring an overall increased patients’ survival
Summary
Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide [1]. Taxanes are potent cytotoxic microtubule-stabilizing agents [4,5,6,7], which interact with beta-tubulin and arrest cells at G2/M phase, blocking normal spindle assembly and cell division. They are widely used in the treatment of breast, ovarian, lung, and head and neck cancers [8,9,10,11]. Paclitaxel offers significant benefits in overall and disease-free survival in metastatic and earlystage cancers [12], and it is given as neoadjuvant treatment [13]. Some patients are insensitive to paclitaxel-based therapy and no biomarker is currently available to adequately identify patients that are less www.impactjournals.com/oncotarget likely to be sensible to taxanes treatment, preventing unnecessary side effects
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