Abstract P2-04-06: Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low Breast Cancer

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Abstract Introduction: CD44 expression is implicated in various signaling pathways and has been reported to influence cancer proliferation and invasion. Claudin-low breast cancer is characterized by the properties of cancer stem cells, specifically CD44+/CD24- phenotype, and exhibits high expression of EMT markers. We focused on the involvement of CD44 and TGF-β receptors in EMT, investigating the combined effect of CD44 suppression and TGF-β receptor inhibitors in Claudin-low breast cancer. Our aim was to evaluate the potential of this dual approach as a novel therapeutic strategy for Claudin-low breast cancer. Materials and Methods: We utilized the claudin-low breast cancer cell lines SUM159 and MDA-MB-231 to establish CD44 knockdown cells. The effects of CD44 knockdown and TGF-β receptor inhibitors on proliferation, invasion, and downstream signaling were investigated. Additionally, the potential synergistic effects of CD44 suppression combined with TGF-β receptor inhibitors were examined. Results: CD44 was found to interact with TGF-β receptor I, but not with TGF-β receptor II. Additionally, CD44 knockdown did not affect the expression levels of TGF-β receptor I/II. In both SUM159 and MDA-MB-231 cells, CD44 knockdown resulted in suppressed proliferation, yet invasion was not inhibited, and phosphorylation of Smad2 was enhanced. However, when combined with TGF-β receptor inhibitors, CD44 knockdown led to synergistic suppression of proliferation, inhibition of invasion, and complete control of Smad2 phosphorylation. Conclusion: In CD44-positive Claudin-low breast cancer cells, CD44 knockdown exhibited a proliferation-suppressive effect. The addition of TGF-β receptor inhibitors produced a synergistic effect in proliferation suppression and controlled Smad2 phosphorylation, thereby inhibiting invasion. This suggests that targeting CD44 in combination with TGF-β receptor inhibitors could provide a novel therapeutic strategy for Claudin-low breast cancer. Citation Format: Ryoichi Matsunuma, Sae Imada, Shoko Sato, Ryosuke Hayami, Michiko Tsuneizumi. Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-06.

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