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p63 isoforms in triple-negative breast cancer: ΔNp63 associates with the basal phenotype whereas TAp63 associates with androgen receptor, lack of BRCA mutation, PTEN and improved survival

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Abstract

The TP63 gene encodes two major protein variants that differ in their N-terminal sequences and have opposing effects. In breast, ΔNp63 is expressed by immature stem/progenitor cells and mature myoepithelial/basal cells and is a characteristic feature of basal-like triple-negative breast cancers (TNBCs). The expression and potential role of TAp63 in the mammary gland and breast cancers is less clear, partly due to the lack of studies that employ p63 isoform-specific antibodies. We used immunohistochemistry with ΔNp63-specific or TAp63-specific monoclonal antibodies to investigate p63 isoforms in 236 TNBCs. TAp63, but not ΔNp63, was seen in tumour-associated lymphocytes and other stromal cells. Tumour cells showed nuclear staining for ΔNp63 in 17% of TNBCs compared to 7.3% that were positive for TAp63. Whilst most TAp63+ tumours also contained ΔNp63+ cells, the levels of the two isoforms were independent of each other. ΔNp63 associated with metaplastic and medullary cancers, and with a basal phenotype, whereas TAp63 associated with androgen receptor, BRCA1/2 wild-type status and PTEN positivity. Despite the proposed effects of p63 on proliferation, Ki67 did not correlate with either p63 isoform, nor did they associate with p53 mutation status. ΔNp63 showed no association with patient outcomes, whereas TAp63+ patients showed fewer recurrences and improved overall survival. These findings indicate that both major p63 protein isoforms are expressed in TNBCs with different tumour characteristics, indicating distinct functional activities of p63 variants in breast cancer. Analysis of individual p63 isoforms provides additional information into TNBC biology, with TAp63 expression indicating improved prognosis.

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Funding

This work was funded by grants MEYS-NPSI-LO1413 and Award LM15089 from the Ministry of Education, Youth and Sports, Czech Republic; GACR P206/12/G151 from the Grant Agency of the Czech Republic; and MH CZ-DRO (MMCI 00209805) from the Ministry of Health, Czech Republic. The funders did not have a role in the planning, performing or analysing the data, or in manuscript preparation or submission.

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Authors and Affiliations

  1. RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 656 53, Brno, Czech Republic

    Philip J. Coates, Rudolf Nenutil, Jitka Holcakova, Marta Nekulova & Borivoj Vojtesek

  2. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic

    Jan Podhorec & Marek Svoboda

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  1. Philip J. Coates
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  2. Rudolf Nenutil
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  3. Jitka Holcakova
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  4. Marta Nekulova
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  7. Borivoj Vojtesek
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Correspondence to Philip J. Coates or Borivoj Vojtesek.

Ethics declarations

All patient data were anonymised, and the study was performed retrospectively on redundant excess tissues following ethical approval by the Biobanking and Biomolecular resources Research Infrastructure (BBMRI) at MMCI, in accordance with European Union regulations and the Declaration of Helsinki.

Conflict of interest

BV is a consultant for and RN is a co-owner of Moravian Biotechnology, who produces the p63 isoform-specific antibodies used in this study. The company did not provide financial support or have any influence over the design or execution of the studies. All other authors declare that they have no conflicts of interest.

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Coates, P.J., Nenutil, R., Holcakova, J. et al. p63 isoforms in triple-negative breast cancer: ΔNp63 associates with the basal phenotype whereas TAp63 associates with androgen receptor, lack of BRCA mutation, PTEN and improved survival. Virchows Arch 472, 351–359 (2018). https://doi.org/10.1007/s00428-018-2324-2

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  • DOI: https://doi.org/10.1007/s00428-018-2324-2

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