∆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)

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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
Number of pages11
JournalJournal of Pathology: Clinical Research
Early online date7 Oct 2019
DOIs
Publication statusE-pub ahead of print - 7 Oct 2019

Keywords

  • p63
  • ∆Np63
  • p40
  • breast
  • cancer stem cells
  • oestrogen receptor
  • HER2
  • aldehyde dehydrogenase
  • CD44
  • ΔNp63
  • Delta Np63

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    Liu, Y., Nekulova, M., Nenutil, R., Horakova, I., Appleyard, M. V., Murray, K., Holcakova, J., Galoczova, M., Quinlan, P., Jordan, L. B., Purdie, C. A., Vojtesek, B., Thompson, A. M., & Coates, P. J. (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