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 subpopulation 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 subpopulation 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.

• Klíčová slova
• CD44, HER2, aldehyde dehydrogenase, breast, cancer stem cells, oestrogen receptor, p40, p63, ΔNp63,
• MeSH
• fenotyp MeSH
• heterografty MeSH
• lidé MeSH
• myši MeSH
• nádorové biomarkery analýza   metabolismus   MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• receptor erbB-2 genetika   metabolismus   MeSH
• receptory pro estrogeny genetika   metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ERBB2 protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorové supresorové proteiny MeSH
• receptor erbB-2 MeSH
• receptory pro estrogeny MeSH
• TP63 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

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.

• Klíčová slova
• Androgen receptor, BRCA1, BRCA2, PTEN, TAp63, Triple-negative breast cancer, ΔNp63,
• MeSH
• fenotyp MeSH
• fosfohydroláza PTEN genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   MeSH
• mutace genetika   MeSH
• nádorové supresorové proteiny genetika   MeSH
• protein - isoformy genetika   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• transkripční faktory genetika   MeSH
• triple-negativní karcinom prsu genetika   metabolismus   mortalita   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• fosfohydroláza PTEN MeSH
• nádorové supresorové proteiny MeSH
• protein - isoformy MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH
• PTEN protein, human MeSH Prohlížeč
• TP63 protein, human MeSH Prohlížeč
• transkripční faktory MeSH