Targeting claudin-4 enhances chemosensitivity of triple negative breast cancer

Abstract Background Triple negative breast cancer (TNBC) possesses highly aggressive phenotype, treatment with limited options, and a poor prognosis. In this study, we examined the therapeutic effect of anti-claudin (CLDN)-4 extracellular domain antibody, 4D3, on TNBC. Methods The expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 78 IDCs (from 2004 to 2009 in a single center). CLDN expression and the effect of 4D3 on proliferation were examined in in human IDC cell lines MCF-7 (luminal subtype) and MDA-468 (TNBC). Results In IDC cases, CLDN1 had lower expression than CLDN4 and correlated with histological grade. In contrast, expression of CLDN4 correlated with histological grade, receptor subtype, and stage. CLDN4 expression in the two cells was at the same level. In both cells, paclitaxel (PTX)-induced growth suppression was enhanced by 4D3. Furthermore, 4D3 increased both intracellular PTX concentration (in both cells) and apoptosis. In the mouse model, 4D3 promoted the antitumor effect of PTX on subcutaneous tumors and reduced lung metastasis. The combination of PTX and 4D3 reduced M2 macrophages and mesenchymal stem cells in the tumor. 4D3 also reduced stemness of the tumors in association with increase in the intratumoral pH. Moreover, concurrent treatment of 4D3, PTX, or tamoxifen; or with PTX and tamoxifen in MDA-468 also showed the same level of antitumor activity and survival as MCF-7. Furthermore, in bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Conclusions CLDN4 targeting of the antibody facilitated existing therapeutic effects.