AI Article Synopsis
- The study investigates the role of phospho-Ser294 progesterone receptors (p-PR) in estrogen receptor-positive (ER+) breast cancer, finding that this receptor modification is linked to worse patient outcomes and increased tumor growth.
- Analysis of tumors and metastatic lesions revealed that activated p-PR correlates with high expression of insulin receptor substrates (IRS-1) and a loss of insulin growth factor receptor (IGF1R), contributing to treatment resistance.
- The research suggests that targeting the interaction between p-PR and IRS-1 could be a viable strategy to combat endocrine resistance in breast cancer.
Article Abstract
Background: Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action.
Methods: The transcriptomes of primary tumours and metastases in mice harbouring ER+ breast cancer patient-derived xenografts (PDXs) were analysed following single-cell RNAseq. In vitro assays were employed to delineate mechanisms of endocrine resistance and stemness.
Results: A 16-gene phospho-Ser294 PR (p-PR) signature predicted poor outcome in ER+ breast cancer. Relative to primary PDX tumours, metastatic lesions expressed abundant p-PR and exhibited an activated PR gene programme with elevated expression of PGR and IRS-1. Breast cancer models of activated PR lost the expression of IGF1R and acquired insulin hypersensitivity with tamoxifen insensitivity. Activated p-PR+ breast cancer cells formed increased tumourspheres with enlarged ALDH+ and CD24-/CD44 populations. E2 induced PR/IRS-1 interaction and exchange of IGF1Rβ for IRS-1 in p-PR-containing transcriptional complexes. Inhibition of IRS-1 or IR and inducible IRS-1 knockdown reduced tumourspheres. Endocrine-resistant models of luminal B breast cancer induced p-PR in 3D cultures and required PR and IRS-1 for tumoursphere formation.
Conclusions: Phospho-PR-B cooperates with IRS-1 to promote outgrowth of endocrine-resistant and stem-like breast cancer cells. Targeting phospho-PR/IRS-1 crosstalk may block the emergence of endocrine resistance.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782753 | PMC |
| http://dx.doi.org/10.1038/s41416-020-01094-y | DOI Listing |
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