Marine Geoffroy1,2, Alexandra Kleinclauss1,2, Stéphanie Grandemange1,2, Sébastien Hupont3, Michel Boisbrun4,5, Stéphane Flament1,2, Isabelle Grillier-Vuissoz6,7, Sandra Kuntz1,2. 1. Université de Lorraine, CRAN, UMR 7039, 54506, Vandœuvre-lès-Nancy, France. 2. CNRS, CRAN, UMR 7039, 54506, Vandœuvre-lès-Nancy, France. 3. CNRS, FR3209 Biologie Moléculaire Cellulaire et Thérapeutique (BMCT), Plateforme d'Imagerie Cellulaire et Tissulaire PTIBC-IBISA, Biopôle de l'Université de Lorraine, Campus Biologie-Santé, 54506, Vandœuvre-lès-Nancy, France. 4. Université de Lorraine, SRSMC, UMR 7565, 54506, Vandœuvre-lès-Nancy, France. 5. CNRS, SRSMC, UMR 7565, 54506, Vandœuvre-lès-Nancy, France. 6. Université de Lorraine, CRAN, UMR 7039, 54506, Vandœuvre-lès-Nancy, France. isabelle.grillier-vuissoz@univ-lorraine.fr. 7. CNRS, CRAN, UMR 7039, 54506, Vandœuvre-lès-Nancy, France. isabelle.grillier-vuissoz@univ-lorraine.fr.
Abstract
PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION: Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.
PURPOSE: 40% of triple-negative breast cancer (TNBC) do not express claudin-1, a major constituent of tight junction. Patients with these "claudin-1-low" tumors present a higher relapse incidence. A major challenge in oncology is the development of innovative therapies for such poor prognosis tumors. In this context, we study the anticancer effects of ∆2-TGZ, a compound derived from troglitazone (TGZ), on cell models of these tumors. METHODS AND RESULTS: In MDA-MB-231 and Hs578T "claudin-1-low" TNBC cells, Δ2-TGZ treatment induced claudin-1 protein expression and triggered apoptosis as measured by FACS analysis (annexin V/PI co-staining). Interestingly, in the non-tumorigenic human breast epithelial cell line MCF-10A, the basal level of claudin-1 was not modified following Δ2-TGZ treatment, which did not induce apoptosis. Furthermore, claudin-1-transfected MDA-MB-231 and Hs578T cells displayed a significant increase of cleaved PARP-1 and caspase 7, caspase 3/7 activities, and TUNEL staining. RNA interference was performed in order to inhibit Δ2-TGZ-induced claudin-1 expression in both the cells. In absence of claudin-1, a decrease of cleaved PARP-1 and caspase 7 and caspase 3/7 activities were observed in MDA-MB-231 but not in Hs578T cells. CONCLUSION:Claudin-1 overexpression and Δ2-TGZ treatment are associated to apoptosis in MDA-MB-231 and Hs578T "claudin-1-low" TNBC. Moreover, in MDA-MB-231 cells, claudin-1 is involved in the pro-apoptotic effect of Δ2-TGZ. Our results suggest that claudin-1 re-expression could be an interesting therapeutic strategy for "claudin-1-low" TNBC.
Entities:
Keywords:
Apoptosis; Claudin-1; Triple-negative breast cancer; Troglitazone derivatives
Authors: Chidalu A Edechi; Maryam Amini; Mohammad K Hamedani; Lucas E L Terceiro; Barbara E Nickel; Etienne Leygue; Yvonne Myal Journal: J Histochem Cytochem Date: 2021-10-29 Impact factor: 2.479