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Updated: Oct 26, 2025
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Published on: May 18, 2020
Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of
Oukseub Lee1, Maarten C Bosland2, Minhua Wang1
1Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract:
Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.
Insights
Selective progesterone receptor modulators (SPRMs) show promise for reducing breast cancer risk in BRCA1 mutation carriers. Ulipristal acetate (UPA) was most effective, reducing tumors and increasing latency in mouse models.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- BRCA1 mutations significantly increase breast cancer risk.
- Progesterone signaling dysregulation is implicated in BRCA1-deficient tumorigenesis.
- Selective progesterone receptor modulators (SPRMs) are potential chemopreventive agents for BRCA1 carriers.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of different SPRMs in a BRCA1-deficient mouse model.
- To investigate the molecular mechanisms underlying SPRM efficacy in preventing BRCA1-associated mammary tumors.
Main Methods:
- Utilized a mouse model with a conditional knockout of the Brca1 C-terminal domain.
- Administered telapristone acetate (TPA), ulipristal acetate (UPA), and mifepristone (MFP) to assess chemopreventive effects.
- Performed RNA sequencing to analyze gene expression changes in response to SPRM treatment.
Main Results:
- SPRMs exhibited varying efficacy: UPA was most effective, followed by TPA, with MFP being ineffective.
- UPA significantly reduced tumorigenesis and increased tumor latency compared to controls.
- UPA treatment decreased proliferation marker Ki67 and increased progesterone receptor (PR) expression in mammary glands.
- RNA sequencing revealed distinct gene expression profiles for UPA and MFP, with UPA downregulating glycolysis and inflammation-related genes.
Conclusions:
- Epithelial progesterone receptor (PR) signaling and its paracrine effects on the microenvironment are crucial in BRCA1-deficient mammary tumorigenesis and prevention.
- Ulipristal acetate (UPA) demonstrates significant potential as a chemopreventive agent for BRCA1-deficient breast cancer.
- The anti-glucocorticoid activity of mifepristone (MFP) does not appear to be tumor-protective in this context.
