∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers

Yajing Liu, Marta Nekulova, Rudolf Nenutil, Iva Horakova, M. Virginia Appleyard, Karen Murray, Jitka Holcakova, Michaela Galoczova, Philip Quinlan, Lee B. Jordan, Colin A. Purdie, Borivoj Vojtesek, Alastair M. Thompson (Lead / Corresponding author), Philip J. Coates (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell sub-population in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41% of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small sub-population of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Pathology: Clinical Research
Early online date7 Oct 2019
DOIs
Publication statusE-pub ahead of print - 7 Oct 2019

Fingerprint

Neoplastic Stem Cells
Mesenchymal Stromal Cells
Breast Neoplasms
Phenotype
Neoplasms
Population
adjuvant P40
Triple Negative Breast Neoplasms
Cell Line
Human Mammary Glands
Heterografts
Protein Isoforms
Stem Cells
Epithelium
Immunohistochemistry
Maintenance

Keywords

  • p63
  • ∆Np63
  • p40
  • breast
  • cancer stem cells
  • oestrogen receptor
  • HER2
  • aldehyde dehydrogenase
  • CD44

Cite this

Liu, Yajing ; Nekulova, Marta ; Nenutil, Rudolf ; Horakova, Iva ; Appleyard, M. Virginia ; Murray, Karen ; Holcakova, Jitka ; Galoczova, Michaela ; Quinlan, Philip ; Jordan, Lee B. ; Purdie, Colin A. ; Vojtesek, Borivoj ; Thompson, Alastair M. ; Coates, Philip J. / ∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers. In: Journal of Pathology: Clinical Research. 2019.
@article{ba2e879098e64915bc7ac0359d04c4ba,
title = "∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers",
abstract = "ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell sub-population in 100 of 173 (58{\%}) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41{\%} of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1{\%} of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small sub-population of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers. This article is protected by copyright. All rights reserved.",
keywords = "p63, ∆Np63, p40, breast, cancer stem cells, oestrogen receptor, HER2, aldehyde dehydrogenase, CD44",
author = "Yajing Liu and Marta Nekulova and Rudolf Nenutil and Iva Horakova and Appleyard, {M. Virginia} and Karen Murray and Jitka Holcakova and Michaela Galoczova and Philip Quinlan and Jordan, {Lee B.} and Purdie, {Colin A.} and Borivoj Vojtesek and Thompson, {Alastair M.} and Coates, {Philip J.}",
note = "This work was supported by the Grant Agency of the Czech Republic (19-06530S); MEYS-NPS I - LO1413; MH CZ-DRO (MMCI 00209805); and by Breast Cancer Research Scotland. YL was supported by a University of Dundee PhD studentship. The MMCI biobank is supported by grant LM2015089 from the Ministry of Education, Youth and Sports, Czech Republic and co-funded by ADOPT BBMRI-ERIC, supported by EU Horizon 2020 (grant agreement No. 676550).",
year = "2019",
month = "10",
day = "7",
doi = "10.1002/cjp2.149",
language = "English",
journal = "Journal of Pathology: Clinical Research",
issn = "2056-4538",
publisher = "Wiley",

}

Liu, Y, Nekulova, M, Nenutil, R, Horakova, I, Appleyard, MV, Murray, K, Holcakova, J, Galoczova, M, Quinlan, P, Jordan, LB, Purdie, CA, Vojtesek, B, Thompson, AM & Coates, PJ 2019, '∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers', Journal of Pathology: Clinical Research. https://doi.org/10.1002/cjp2.149

∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers. / Liu, Yajing; Nekulova, Marta; Nenutil, Rudolf; Horakova, Iva; Appleyard, M. Virginia; Murray, Karen; Holcakova, Jitka; Galoczova, Michaela; Quinlan, Philip; Jordan, Lee B.; Purdie, Colin A.; Vojtesek, Borivoj; Thompson, Alastair M. (Lead / Corresponding author); Coates, Philip J. (Lead / Corresponding author).

In: Journal of Pathology: Clinical Research, 07.10.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers

AU - Liu, Yajing

AU - Nekulova, Marta

AU - Nenutil, Rudolf

AU - Horakova, Iva

AU - Appleyard, M. Virginia

AU - Murray, Karen

AU - Holcakova, Jitka

AU - Galoczova, Michaela

AU - Quinlan, Philip

AU - Jordan, Lee B.

AU - Purdie, Colin A.

AU - Vojtesek, Borivoj

AU - Thompson, Alastair M.

AU - Coates, Philip J.

N1 - This work was supported by the Grant Agency of the Czech Republic (19-06530S); MEYS-NPS I - LO1413; MH CZ-DRO (MMCI 00209805); and by Breast Cancer Research Scotland. YL was supported by a University of Dundee PhD studentship. The MMCI biobank is supported by grant LM2015089 from the Ministry of Education, Youth and Sports, Czech Republic and co-funded by ADOPT BBMRI-ERIC, supported by EU Horizon 2020 (grant agreement No. 676550).

PY - 2019/10/7

Y1 - 2019/10/7

N2 - ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell sub-population in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41% of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small sub-population of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers. This article is protected by copyright. All rights reserved.

AB - ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell sub-population in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41% of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small sub-population of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers. This article is protected by copyright. All rights reserved.

KW - p63

KW - ∆Np63

KW - p40

KW - breast

KW - cancer stem cells

KW - oestrogen receptor

KW - HER2

KW - aldehyde dehydrogenase

KW - CD44

U2 - 10.1002/cjp2.149

DO - 10.1002/cjp2.149

M3 - Article

C2 - 31591823

JO - Journal of Pathology: Clinical Research

JF - Journal of Pathology: Clinical Research

SN - 2056-4538

ER -