Abstract LB-64: Synuclein gamma inhibits BubR1 function and renders resistance to antimicrotubule drug

Abstract

Abstract The microtubule (MT) cytoskeleton is an effective and validated target for cancer chemotherapeutic drugs. Currently, anti-MT drug taxane, e.g. docetaxel, is the first-line chemotherapeutic agent to treat patients with locally advanced or metastatic breast cancer and is also one of the most effective chemotherapeutic agents in clinical use in six different cancers (breast, ovarian, non-small cell lung, prostate, gastric, and head and neck). Nearly half of the treated breast and ovarian cancer patients, however, do not respond to chemotherapy. Although general mechanisms of drug resistance may apply to docetaxel resistance, more specifically, the current research paradigm on docetaxel resistance focus on acquired -tubulin mutations and altered expression of β-tubulin isotypes that interfere with drug target binding. Synuclein gamma (SNCG) is a new unfavorable prognostic marker for breast cancer and a potential target for cancer treatment. At the cellular level, SNCG increases metastasis and promotes genetic instability. At the molecular level, SNCG functions like a tumor specific chaperone and regulates many pathways in growth and progression of cancer, including an interaction with mitotic checkpoint kinase BubR1. Here, we show that expression of SNCG is sufficient to induce specific resistance to docetaxel-caused mitotic arrest and apoptosis in breast cancer cells and in breast cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1, interferes with its interaction with other checkpoint proteins of p55cdc20-APC and Mda2, reduces BubR1's kinase activity, and thus attenuates docetaxel-caused mitotic cell death. The working mechanism of anti-MT drugs heavily relies on the normal function of the checkpoint machinery in which BubR1 is a critical component, this inhibitory effect of SNCG on BubR1 function may lead to the inactivation of checkpoint and thus renders docetaxel resistance. To test the clinical relevance, in a pilot neoadjuvant trial, 20 women with histological proven locally advanced breast cancer were treated with 3 cycles of neoadjuvant TE regimen (docetaxel + epirubicin). SNCG-positive tumors are resistant to anticancer effect of neoadjuvant therapy as assayed by reduction in primary tumor size, an increase in apoptotic index, and a decrease in Ki67 proliferation index. These data show that SNCG renders docetaxel resistance by inhibiting BubR1 activity and is new biomarker for predicting anti-MT drug resistance. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-64.