ABSTRACT
Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15-20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic. Little is known about CLDN1 role on the chemosensitivity of breast cancer. Our clinical data analysis reveals that CLDN1 low expression is correlated to a poor prognostic in TNBC patients. Next, the sensitivity of various TNBC "claudin-1-high" or "claudin-1-low" cells to three compounds belonging to the main class of chemotherapeutic agents commonly used for the treatment of TNBC patients: 5-fluorouracil (5-FU), paclitaxel (PTX) and doxorubicin (DOX). Using RNA interference and stable overexpressing models, we demonstrated that CLDN1 expression increased the sensitivity of TNBC cell lines to these chemotherapeutic agents. Taken together, our data established the important role of CLDN1 in TNBC cells chemosensitivity and supported the hypothesis that CLDN1 could be a chemotherapy response predictive marker for TNBC patients. This study could allow new treatment protocols creation aimed to induce CLDN1 expression in TNBCs to increase their sensitivity to chemotherapy.
ABSTRACT
Breast cancer is one of the leading causes of cancer-related death among females worldwide. A major challenge is to develop innovative therapy in order to treat breast cancer subtypes resistant to current treatment. In the present study, we examined the effects of two Troglitazone derivatives Δ2-TGZ and AB186. Previous studies showed that both compounds induce apoptosis, nevertheless AB186 was a more potent agent. The kinetic of cellular events was investigated by real-time cell analysis system (RTCA) in MCF-7 (hormone dependent) and MDA-MB-231 (triple negative) breast cancer (TNBC) cells, followed by cell morphology analysis by immuno-localization. Both compounds induced a rapid modification of both impedance-based signals and cellular morphology. This process was associated with an inhibition of cell migration measured by wound healing and transwell assays in TNBC MDA-MB-231 and Hs578T cells. In order to identify cytoplasmic targets of AB186, we performed surface plasmon resonance (SPR) and pull-down analyses. Subsequently, 6 cytoskeleton components were identified as potential targets. We further validated α-tubulin as one of the direct targets of AB186. In conclusion, our results suggested that AB186 could be promising to develop novel therapeutic strategies to treat aggressive forms of breast cancer such as TNBC.
