Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer

Amy R Dwyer,Thu H Truong,Carol A Lange,Peter Kabos,Carlos Perez Kerkvliet,Carol A Sartorius,Kiran V Paul

doi:10.1038/s41416-020-01094-y

Abstract

BackgroundProgesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action.MethodsThe 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.ResultsA 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.ConclusionsPhospho-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.

Highlights

Progesterone receptors (PR) are potent modifiers of endocrine responses
Phospho-PR target genes correlate with poor outcome in clinical breast cancer We previously identified distinct 151-gene ligand-dependent and 92-gene ligand-independent (LI) phospho-PR-specific gene signatures that were both associated with human epidermal growth factor-2 (ERB2/Her2)-positive luminal breast cancers as defined by Oncomine concepts.[13]
Phospho-PR-B and Insulin receptor substrate-1 (IRS-1) are preferentially co-recruited to E2regulated genes We previously reported a requirement for PR-B expression and the presence of express oestrogen receptor (ER)/PR/PELP1 and ER/PR/IGF1Rβ complexes at specific steroid receptor target genes, including CTSD26 in response to oestrogen stimulation; cathepsin D (CTSD) expression is associated with increased risk of relapse and metastasis.[37]

Summary

Introduction

Progesterone receptors (PR) are potent modifiers of endocrine responses. In aberrant signalling cancer contexts, phosphorylation events dramatically alter steroid hormone receptor action. 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. 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. Inevitable emergence of breast cancers that are both endocrine and CDK4/6 inhibitor resistant is a major concern.[4,5] endocrine resistance remains a key clinical problem and there is a need to identify novel strategies to prevent, delay, or reverse/overcome resistance to endocrine therapy.

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