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

doi:10.1038/s41416-020-01094-y

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

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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.

Original language	English (US)
Pages (from-to)	217-227
Number of pages	11
Journal	British Journal of Cancer
Volume	124
Issue number	1
DOIs	https://doi.org/10.1038/s41416-020-01094-y
State	Published - 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.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.

Keywords

Animals
Antineoplastic Agents, Hormonal/pharmacology
Breast Neoplasms/metabolism
Drug Resistance, Neoplasm/physiology
Female
Heterografts
Humans
Insulin Receptor Substrate Proteins/metabolism
Mice
Neoplastic Stem Cells/metabolism
Receptors, Estrogen/metabolism
Receptors, Progesterone/metabolism

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41416-020-01094-y

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

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.",

keywords = "Animals, Antineoplastic Agents, Hormonal/pharmacology, Breast Neoplasms/metabolism, Drug Resistance, Neoplasm/physiology, Female, Heterografts, Humans, Insulin Receptor Substrate Proteins/metabolism, Mice, Neoplastic Stem Cells/metabolism, Receptors, Estrogen/metabolism, Receptors, Progesterone/metabolism",

author = "Dwyer, {Amy R.} and Truong, {Thu H.} and Kerkvliet, {Carlos Perez} and Paul, {Kiran V.} and Peter Kabos and Sartorius, {Carol A.} and Lange, {Carol A.}",

note = "Funding Information: Funding information This work was supported by the National Institutes of Health{\textquoteright}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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Cancer Research UK.",

year = "2021",

month = jan,

day = "5",

doi = "10.1038/s41416-020-01094-y",

language = "English (US)",

volume = "124",

pages = "217--227",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Insulin receptor substrate-1 (IRS-1) mediates progesterone receptor-driven stemness and endocrine resistance in oestrogen receptor+ breast cancer

AU - Dwyer, Amy R.

AU - Truong, Thu H.

AU - Kerkvliet, Carlos Perez

AU - Paul, Kiran V.

AU - Kabos, Peter

AU - Sartorius, Carol A.

AU - Lange, Carol A.

N1 - 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. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Cancer Research UK.

PY - 2021/1/5

Y1 - 2021/1/5

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents, Hormonal/pharmacology

KW - Breast Neoplasms/metabolism

KW - Drug Resistance, Neoplasm/physiology

KW - Female

KW - Heterografts

KW - Humans

KW - Insulin Receptor Substrate Proteins/metabolism

KW - Mice

KW - Neoplastic Stem Cells/metabolism

KW - Receptors, Estrogen/metabolism

KW - Receptors, Progesterone/metabolism

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U2 - 10.1038/s41416-020-01094-y

DO - 10.1038/s41416-020-01094-y

M3 - Article

C2 - 33144693

AN - SCOPUS:85094981817

SN - 0007-0920

VL - 124

SP - 217

EP - 227

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 1

ER -

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

Abstract

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Keywords

PubMed: MeSH publication types

UN SDGs

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