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, Carlos Perez Kerkvliet, Kiran V. Paul, Peter Kabos, Carol A. Sartorius, Carol A. Lange

Research output: Contribution to journalArticlepeer-review

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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalBritish Journal of Cancer
Volume124
Issue number1
DOIs
StatePublished - Jan 5 2021

Bibliographical note

Funding Information:
Funding information This work was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494 (to A.R.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. This work was additionally supported by NIH grants R01 CA159712 (to C.A.L.) and CA229697 (to C.A.L. and C.A.S.), F32 CA210340 (to T.H.T.), T32 HL007741 (to T.H.T.), F30 CA228261 (to C.P.K.), T32 CA009138 (to C.P.K.), and R01 CA140985 (to C.A.S.). Breast Cancer Research Foundation 16-072 (to C.A.S.) and the Tickle Family Land Grant Endowed Chair in Breast Cancer Research (to C.A.L.) also supported this work.

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