Progesterone Receptor Signaling in Breast Cancer

Progesterone receptor (PR) signalling plays a multifaceted role in breast cancer, integrating genomic and non‐genomic pathways to influence tumour initiation, progression and therapeutic response. PR exists primarily as two isoforms, PRA and PRB, which differentially regulate gene networks related to cell proliferation, survival, extracellular matrix remodelling and stem cell fate. Ligand binding induces PR dimerisation, chromatin recruitment to progesterone response elements and interactions with coactivators or corepressors, thereby modulating transcription of target genes. Concurrently, PR engages rapid signalling cascades via cSrc, MAPK and PI3K pathways, often enhanced by post-translational modifications such as phosphorylation and SUMOylation. Cross-talk with oestrogen receptor (ER) pathways is bidirectional: ER controls PR expression, while PR activity can reprogram ER‐driven transcription. Dysregulation of PR isoform ratios, heightened PR phosphorylation or aberrant coregulator expression are linked to more aggressive phenotypes, increased metastatic potential and therapy resistance. Preclinical models demonstrate that PR modulates breast cancer cell proliferation, migration and stem cell properties, underscoring its relevance as both a prognostic marker and therapeutic target. Advances in molecular tools, transcriptomic profiling and pharmacological modulation are refining our understanding of PR biology and opening avenues for personalised endocrine therapies that combine antiprogestins with current standards to improve outcomes and prevent recurrence.

Research from Nature Portfolio

Computational approaches have accelerated the design of small-molecule PR inhibitors. Pharmacophore-based virtual screening of natural product libraries identified lead compounds that bind the human PR ligand‐binding domain with high stability and favourable energetics, offering structural blueprints for next-generation antiprogestins. In vivo and in silico validation of top candidates supports their potential to selectively antagonise PR activity in breast cancer cells, laying the groundwork for targeted drug development. Complementary genetic studies using patient-derived ER+ breast tumour xenografts reveal that progesterone alone drives tumour growth and metastasis in a patient-specific manner. Progesterone responses correlate with distinct oncogenic signatures, including MYC and androgen receptor pathways. Ablation of PR expression in these models halts tumour progression even when oestrogen signalling is intact, highlighting PR as a critical driver and a promising therapeutic vulnerability.

Progesterone Receptor Signaling in Breast Cancer publication trend

The graph below shows the total number of articles in progesterone receptor signaling in breast cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Progesterone receptor (PR): A nuclear hormone receptor that mediates progesterone’s effects via transcriptional regulation and rapid signalling cascades.

PRA and PRB isoforms: Alternative PR forms differing by N-terminal sequence; they regulate distinct gene sets and influence breast cancer biology.

Antiprogestin: A compound that binds PR and inhibits its activation, used to block progesterone-driven tumour growth.

Pharmacophore-based virtual screening: A computational method to identify candidate molecules that share key features necessary for binding a target receptor.

Xenograft: A model in which human tumour cells are implanted into immunocompromised mice to study cancer biology and therapeutic responses.

References

1. Transcriptomic Profile of Breast Tissue of Premenopausal Women Following Treatment with Progesterone Receptor Modulator: Secondary Outcomes of a Randomized Controlled Trial. International Journal of Molecular Sciences (2024).
2. Steroid profile in patients with breast cancer and in mice treated with mifepristone. Endocrine Related Cancer (2023).
3. Targeting human progesterone receptor (PR), through pharmacophore-based screening and molecular simulation revealed potent inhibitors against breast cancer. Scientific Reports (2024).
4. A molecular toolbox to study progesterone receptor signaling. Journal of Mammary Gland Biology and Neoplasia (2023).
5. Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells*. Journal of Biological Chemistry (2001).
6. Progesterone receptors - animal models and cell signaling in breast cancer: The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Research (2002).
7. Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs. Journal of Hematology & Oncology (2017).
8. Phosphorylated and sumoylation-deficient progesterone receptors drive proliferative gene signatures during breast cancer progression. Breast Cancer Research (2012).
9. Estrogen receptor positive breast cancers have patient specific hormone sensitivities and rely on progesterone receptor. Nature Communications (2022).
10. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling. Oncotarget (2017).
11. Molecular determinants of context-dependent progesterone receptor action in breast cancer. BMC Medicine (2014).