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

Shaimaa Hamza1, Ekaterina E Garanina1, Mohammad Alsaadi1

  • 1Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia.

International Journal of Molecular Sciences
|March 11, 2023
PubMed

Insights

Blocking estrogen receptor-alpha (ER-α) in breast cancer (BC) activates NLRP3 inflammasome, increasing BC cell aggressiveness. This suggests a link between ER-α targeted therapies and NLRP3 activation in BC progression.

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.
Keywords:
NLRP3breast cancerestrogen receptor alphamifepristoneprogesterone receptortamoxifen

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