Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple-negative breast cancers
Yu-Wei Hsiao1, Jhih-Ying Chi1, Chien-Feng Li2
1Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan R. O. C.
Abstract:
Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple-negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF-β1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF-κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA-MB-231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA-MB-231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.
Insights
Targeting pentraxin 3 (PTX3) in cancer stroma offers a new therapeutic strategy. Inhibiting the PTX3/CD44 interaction significantly reduced triple-negative breast cancer growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Cancer cells exhibit genetic heterogeneity, making targeting tumor microenvironment stromal cells a promising therapeutic approach.
- Pentraxin 3 (PTX3) in stromal cells is a potential therapeutic target, but its regulatory mechanisms require investigation.
Purpose of the Study:
- To investigate the role of stromal PTX3 in cancer progression and its potential as a therapeutic target.
- To elucidate the regulatory pathway of PTX3 expression and its downstream signaling in triple-negative breast cancer (TNBC).
Main Methods:
- In vivo studies to assess the impact of PTX3 loss on cancer growth and metastasis.
- Analysis of clinical data correlating stromal PTX3 expression with patient outcomes in TNBC.
- Investigating the induction of PTX3 by transforming growth factor beta 1 (TGF-β1) via CCAAT/enhancer binding protein delta (CEBPD).
- Examining PTX3-CD44 interaction and downstream signaling pathways (ERK1/2, AKT, NF-κB).
- Development and testing of PTX3 inhibitors targeting the PTX3/CD44 interaction.
Main Results:
- Loss of stromal PTX3 significantly inhibited cancer cell metastasis and growth in vivo.
- Elevated stromal PTX3 expression correlated with adverse prognostic features and poorer survival in TNBC patients.
- TGF-β1 induces stromal PTX3 expression through CEBPD activation.
- PTX3, via its receptor CD44, activates ERK1/2, AKT, and NF-κB pathways, promoting TNBC cell metastasis, invasion, and stemness.
- PTX3 inhibitors effectively attenuated cancer cell growth and restricted metastasis/invasion.
Conclusions:
- Stromal PTX3 is a critical factor in TNBC progression and a potential therapeutic target.
- The PTX3/CD44 signaling axis plays a significant role in TNBC metastasis, invasion, and stemness.
- Targeting the PTX3/CD44 interaction represents a novel therapeutic strategy for TNBC.
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