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Published on: February 6, 2015
Targeting claudin-4 enhances chemosensitivity in breast cancer
Yi Luo1,2, Shingo Kishi1, Takamitsu Sasaki1
1Department of Molecular Pathology, Nara Medical University, Nara, Japan.
Abstract:
Triple negative breast cancer (TNBC) is characterized by highly aggressive phenotype, limited treatment options and a poor prognosis. In the present study, we examined the therapeutic effect of anti-claudin (CLDN)-4 extracellular domain antibody, 4D3, on TNBC. When the expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 114 IDC (78 cases from 2004 to 2009 in a single center and 36 cases of tissues array), CLDN1 had lower expression than CLDN4 and was correlated with histological grade. In contrast, expression of CLDN4 was correlated with histological grade, receptor subtype, and stage. CLDN4 expression in human IDC cell lines MCF-7 (luminal subtype) and MDA-468 (TNBC) 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 and increased the intratumoral pH. Moreover, concurrent treatment with 4D3, PTX and tamoxifen, or with PTX and tamoxifen in MDA-468 also showed the same level of antitumor activity and survival as MCF-7. Furthermore, in a bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Thus, CLDN4 targeting of the antibody facilitated existing therapeutic effects.
Insights
This study shows that an anti-claudin 4 antibody (4D3) enhances chemotherapy for triple-negative breast cancer (TNBC). Combining 4D3 with paclitaxel improves tumor suppression and reduces metastasis in preclinical models.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents aggressive characteristics, limited therapeutic options, and poor prognosis.
- Claudin 4 (CLDN4) expression is linked to histological grade, receptor subtype, and stage in invasive ductal carcinoma (IDC).
Purpose of the Study:
- To investigate the therapeutic potential of the anti-claudin 4 (CLDN4) antibody, 4D3, in treating TNBC.
- To evaluate the combined effects of 4D3 and paclitaxel (PTX) on TNBC growth, metastasis, and tumor microenvironment.
Main Methods:
- Examined CLDN4 and CLDN1 expression in 114 IDC samples and human cell lines (MCF-7 and MDA-468).
- Assessed the impact of 4D3 alone and in combination with PTX on cell growth, intracellular PTX concentration, and apoptosis in vitro.
- Evaluated the efficacy of 4D3 and PTX combination therapy in mouse models of subcutaneous tumors and bone metastasis, including analysis of tumor microenvironment components.
Main Results:
- CLDN4 expression correlated with adverse prognostic factors in IDC, while CLDN1 expression was linked to histological grade.
- 4D3 enhanced PTX-induced growth suppression, increased intracellular PTX levels, and promoted apoptosis in both luminal and TNBC cell lines.
- In vivo, 4D3 combined with PTX demonstrated significant antitumor effects, reduced lung metastasis, decreased M2 macrophages and mesenchymal stem cells, lowered tumor stemness, and increased intratumoral pH.
- Combination therapy showed comparable antitumor activity and survival benefits across different cell lines and treatment regimens.
Conclusions:
- CLDN4-targeting antibody 4D3 potentiates the therapeutic effects of existing treatments like paclitaxel for TNBC.
- 4D3 modulates the tumor microenvironment, reducing immunosuppressive cells and enhancing anti-tumor immunity.
- Targeting CLDN4 represents a promising strategy to improve treatment outcomes for triple-negative breast cancer.
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