Blocking the Hormone Receptors Modulates NLRP3 in LPS-Primed Breast Cancer Cells

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• NOD-like receptor protein 3 (NLRP3) inflammasome activation is implicated in breast cancer (BC) progression.
• The influence of key BC biomarkers, including estrogen receptor-alpha (ER-α), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), on NLRP3 activation is not well understood.
• Limited data exist on how blocking these receptors affects NLRP3 expression in BC.

Purpose of the Study:

• To investigate the role of ER-α, PR, and HER2 in NLRP3 inflammasome activation within breast cancer.
• To determine the effect of blocking ER-α, PR, and HER2 on NLRP3 expression and inflammasome activation in BC cell lines.
• To explore the correlation between NLRP3 and ER-α expression in different BC subtypes.

Main Methods:

• Transcriptomic profiling of NLRP3 in BC using GEPIA, UALCAN, and Human Protein Atlas.
• In vitro activation of NLRP3 using lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP) in MCF-7 (luminal A) and MDA-MB-231/HCC1806 (TNBC) cells.
• Treatment with tamoxifen (Tx), mifepristone (mife), and trastuzumab (Tmab) to block ER-α, PR, and HER2, respectively, in LPS-primed MCF7 cells, followed by assessment of inflammasome activation, cell proliferation, migration, and spheroid formation.

Main Results:

• NLRP3 transcript levels correlated with ESR1 (encoding ER-α) in luminal A and TNBC tumors.
• NLRP3 protein expression was higher in MDA-MB-231 cells compared to MCF7 cells, and LPS/ATP treatment reduced proliferation and wound healing in both.
• Blocking ER-α with tamoxifen (Tx) promoted NLRP3 activation, increased migration and spheroid formation, and elevated IL-8 and SCGF-b secretion in MCF7 cells; PR inhibition with mifepristone (mife) opposed NLRP3 activation, while HER2 inhibition with trastuzumab (Tmab) had minimal effect.

Conclusions:

• NLRP3 activation is linked to ER-α status in breast cancer.
• Blocking ER-α with tamoxifen enhances NLRP3 inflammasome activation, promoting aggressive phenotypes like increased migration and proliferation in ER-α-positive BC cells.
• These findings highlight a potential mechanism linking ER-α targeted therapy to increased BC aggressiveness via NLRP3 activation.