CUSP/p63 expression in basal cell carcinoma

Abstract

Chronic ulcerative stomatitis protein (CUSP), the most abundant cutaneous isoform of p63, is a p53-related gene essential for epithelial development. CUSP lacks the N-terminal transactivation domain found on other p53 family members and has been shown to inhibit p53 function in vitro. In this study, biopsies of normal skin (21 of 21), benign neoplasms [seborrheic keratosis (3 of 3), acrochordon (2 of 3), and verruca plana (3 of 3)], and squamous cell carcinomas (SCC) (4 of 4) displayed strong nuclear CUSP immuno-reactivity in epidermal cells. In contrast few basal cell carcinomas (BCC) (7 of 27) and sebaceous nevi (1 of 2) displayed this pattern of CUSP immunoreactivity. Thus, biopsies of cutaneous conditions characterized by sonic hedgehog (SHH) pathway dysregulation were more than 86 times as likely to lack CUSP/p63 immunofluorescence as were other cutaneous samples. Adjacent normal-appearing skin from patients with basal cell nevus syndrome (BCNS) (2 of 3) also lacked CUSP immuno-staining. Lastly, a BCC arising in a patched heterozygous mouse also lacked CUSP immuno-staining. Because CUSP mRNA and protein were detected via Northern and Western analysis in BCC samples lacking CUSP immuno-staining, we sequenced the coding region of CUSP from two non-staining BCCs but found no mutations. Therefore, CUSP appears to be present, unmutated, and yet frequently undetectable by immunofluorescence in cutaneous lesions in both humans and mice that are associated with SHH pathway dysregulation (BCCs, BCNS, and nevus sebaceous).

An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

“…Although both stem cells and ORS cells reside in the basal compartment, and, according to our hypothesis can act as the cellular origin to hedgehog pathway-induced skin tumours, our data show that BCC transformation can occur in basal cells lacking inherent self-renewing potential. Consistent with this suggestion, only 26% of human BCCs exhibit p63 expression (Dellavalle et al, 2002), thus representing the subset of BCCs that arose within the epidermal progenitor compartment.…”

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

“…p63 clearly plays a critical role in epidermal development and homeostasis both in mice and humans (15)(16)(17), but it is still unclear if p63 plays a role in carcinogenesis. While p63 has been reported to be absent or reduced in some human cancers, including basal cell carcinomas (18), it has more frequently been reported to be overexpressed in various tumors (19,20), including non-melanoma skin cancers (21)(22)(23)(24). Similarly, conflicting data from mice heterozygous for p63 have not resolved whether p63 is a tumor suppressor or oncogene (25)(26)(27).…”

p40: A p63 Isoform Useful for Lung Cancer Diagnosis – A Review of the Physiological and Pathological Role of p63

“…Examples of that are breast, prostate, and cutaneous lesions, such as basal cell carcinoma, basal cell nevus syndrome, and nevus sebaceous, which strongly express p63 in normal cells of the basal layer but not in carcinomas [11,37]. In prostate, p63 staining is restricted to the basal cell layer, being a reliable marker of basal cells; however, the vast majority of prostate cancers and pre-invasive prostate intraepithelial neoplasia lesions lose p63 expression, making it an excellent diagnostic marker in prostate cancer which can be used clinically for differential diagnosis [38,39,40].…”