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POR overexpression induces tamoxifen-resistance in breast cancer through the STAT1/c-Myc pathway

Si Chen1, Dingjie Wu1, Qiannan Liu1

  • 1Department of Microbial and Biochemical Pharmacy, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China.

Molecular Carcinogenesis
|November 2, 2022
PubMed

Insights

High NADPH-dependent cytochrome P450 reductase (POR) expression predicts poor outcomes in estrogen receptor-positive breast cancer patients treated with tamoxifen (TAM). POR promotes tamoxifen resistance via the STAT1/c-Myc pathway, suggesting combined therapies for improved treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer is the most common cancer in women globally.
  • Tamoxifen (TAM) resistance is a significant clinical challenge in treating estrogen receptor (ER)-positive breast cancer.
  • The role of NADPH-dependent cytochrome P450 reductase (POR) in TAM resistance is not well understood.

Purpose of the Study:

  • To investigate the role of POR in tamoxifen resistance in ER-positive breast cancer.
  • To identify POR as a potential prognostic biomarker for TAM-treated breast cancer patients.
  • To elucidate the molecular mechanisms underlying POR-induced TAM resistance.

Main Methods:

  • Analysis of POR expression in ER-positive and TAM-treated breast cancer patient cohorts.
  • Cox proportional hazards regression analysis to assess prognostic value.
  • Investigation of POR's role in TAM resistance in ER-positive breast cancer cells.
  • Immunohistochemical analysis of POR and STAT1 expression.
  • Evaluation of combined TAM and STAT1 inhibitor treatment.

Main Results:

  • High POR expression is associated with poor prognosis in ER-positive, TAM-treated breast cancer patients.
  • POR expression is an independent prognostic biomarker for this patient group.
  • POR overexpression promotes TAM resistance by activating the STAT1/c-Myc pathway.
  • High POR/STAT1 expression correlates with poor prognosis in TAM-treated patients.
  • Combined TAM and a STAT1 inhibitor (Fludarabine) show enhanced efficacy against TAM-resistant cells.

Conclusions:

  • POR overexpression induces tamoxifen resistance in ER-positive breast cancer via the STAT1/c-Myc pathway.
  • POR serves as an independent prognostic biomarker in TAM-treated breast cancer.
  • Combining TAM with STAT1 inhibitors represents a promising therapeutic strategy for POR-induced TAM resistance.
Keywords:
NADPH-dependent cytochrome P450 reductase (POR)STAT1/c-Myc pathwaybreast cancerconcomitant drugstamoxifen resistance

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