PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tumor-infiltrating immune cells and hormone receptor (HR) status significantly influence breast cancer (BC) progression.
• Mast cells (MCs) show differential prognostic implications in HR-positive (HR(+)) versus HR-negative (HR(-)) BC.
• The specific molecular mechanisms of MCs in distinct BC subtypes require clarification.

Purpose of the Study:

• To elucidate the distinct roles and molecular mechanisms of mast cells in HR(+) and HR(-) breast cancer.
• To investigate the interaction between hormone receptors, mast cells, and apoptosis in breast cancer.
• To identify potential therapeutic targets for precision medicine in breast cancer treatment.

Main Methods:

• Analysis of mast cell infiltration and its correlation with prognosis in different BC subtypes.
• In vitro studies assessing the effects of MCs on BC cell apoptosis.
• Investigation of the progesterone receptor (PGR)-KIT ligand (KITLG) signaling pathway and MC-derived granulin (GRN) production.
• Experimental manipulation using PGR knockdown and KITLG-cKIT inhibitor (iSCK03) to assess anti-tumor activity.

Main Results:

• Mast cell infiltration is associated with poor prognosis in HR(+) BC and improved prognosis in HR(-) BC.
• HR(-) BC cells undergo apoptosis upon MC stimulation, while HR(+) BC cells exhibit anti-apoptotic effects.
• In HR(+) BC, PGR upregulates KITLG, promoting MC-derived GRN production, which inhibits TNFα-induced apoptosis by binding TNFR1.
• Disrupting PGR-KITLG signaling enhances HR(+) BC cell sensitivity to MC-induced apoptosis and demonstrates anti-tumor activity.

Conclusions:

• The PGR-KITLG-GRN axis in HR(+) BC cells promotes MC-mediated anti-apoptotic effects, contributing to tumor progression.
• Targeting the PGR-KITLG signaling pathway offers a potential strategy to enhance anti-tumor immunity and therapeutic efficacy in HR(+) BC.
• These findings highlight the complex role of mast cells and identify a specific molecular pathway for precision medicine development in breast cancer.