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

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.

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

“…In addition, in this study, we identified TP63, an EMT gene, as a member of a 13-gene signature for overall survival. TP63 isomorphs are reported to be related to different basal phenotypes [ 45 ]. Furthermore, it is known that TP63 regulation via PI3K/Akt and immune response markers promote drug resistance in breast cancer [ 46 ].…”

Perturbing Enhancer Activity in Cancer Therapy

“…The fact that deltaNp63 overexpression was sufficient to activate the squamous program suggests that this transcription factor may be an Achilles heel in this particular subtype [14]. DeltaNp63 was reported to be highly expressed in cancers and molecular subtypes of cancer that are squamous or basal in their nature, such as breast, head and neck, lung, and esophageal carcinoma [197,198,199,200]. We suggest that these findings may serve as a basis and rationale for the next step in precision oncology and the design of future basket trials where the effect of targeting deltaNp63 and its downstream activated enhancers can be investigated in malignancies that are divergent in origin but similar in the enhancer programs that drive their identity and aggressiveness.…”

Pan-p63 but not ΔNp63 (p40) expression in undifferentiated carcinoma of the pancreas

“…Observation of pan-p63-positivity in p40-negative tissues is suggestive of the presence of TAp63 isoform [35,[57][58][59][60]. Gene fusions involving TP63 and TP63 amplifications may influence p63 expression patterns [39,58], but TP63 fusions were not reported in DAin high-grade follicular lymphoma the prevalence of pan-p63-positive cells correlated with TAp63 mRNA expression [59] -TAp63 is an unstable isoform [20], so its mRNA and protein expression levels may not be fully concordant [70]; (9) other markers of squamous differentiation (e.g. CK5/6, CK34βE12, desmocollin-3, desmoglein-3, S100A2, S100A7, SOX2, and glypican-3 [35,77,78,80]) were not examined; however, their diagnostic performance seems to be worse than p40 immunostain, due to compromised specificity or sensitivity [35,77,78,80].…”

“…Gene targets of TAp63 and ΔNp63 are also partially different [18,24]. The distinction of ΔNp63 and TAp63 in clinical samples may be important because p63 expression patterns are associated with clinicopathological features of tumours and long-term prognosis [39,40]. ΔNp63 has a dominant-negative effect on p53 and p63 function [18] because it is able to functionally inactivate p53 [27].…”