p53 and p63 belong to a family of sequence-specific transcription factors regulating key cellular processes. Differential composition of the p53 and p63 DNA-binding sites may contribute to distinct functions of these protein homologues. We used SELEX (systematic evolution of ligands by exponential enrichment) methodology to identify nucleic acid ligands for p63. We found that p63 bound preferentially to DNA fragments conforming to the 20 bp sequence 5 0 -RRRC(A/G)(A/T)GYYYRRRC(A/T) (C/T)GYYY-3 0 . Relative to the p53 consensus, the p63 consensus DNA-binding site (DBS) was more degenerate, particularly at positions 10 and 11, and was enriched for A/G at position 5 and C/T at position 16 of the consensus. The differences in DNA-binding site preferences between p63 and p53 influenced their ability to activate transcription from select response elements (REs) in cells. A computer algorithm, p63MH, was developed to find candidate p63-binding motifs on input sequences. We identified genes responsive to p63 regulation that contain functional p63 REs. Our results suggest that the sequence composition of REs could be one contributing factor to target gene discrimination between p63 and p53.

DNp63a is a nuclear transcription factor that maintains epithelial progenitor cell populations, is overexpressed in several epithelial cancers, and can negatively regulate apoptosis. However, the mechanisms by which DNp63a a promotes cell survival are unclear. DNp63a a has been reported to act as a transcriptional repressor, but specific target genes directly repressed by DNp63a a remain unidentified. Here, we present evidence that DNp63a a functions to negatively regulate the proapoptotic protein IGFBP-3. Disruption of p63 expression in squamous epithelial cells increases IGFBP-3 expression, whereas ectopic expression of DNp63a a down-regulates IGFBP-3. DNp63a a binds to sites in the IGFBP-3 gene in vivo and can modulate transcription through these sites. Furthermore, DNp63a a and IGFBP-3 expression patterns are inversely correlated in normal squamous epithelium and squamous cell carcinomas. These data suggest that IGFBP-3 is a target of transcriptional repression by DNp63a a and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis. (Cancer Res 2005; 65(6): 2314-20)

BACKGROUND:The authors evaluated the clinical characteristics, natural history, and outcomes of patients who had 1 cm, lymph node-negative, triple-negative breast cancer (TNBC). METHODS: After excluding patients who had received neoadjuvant therapy, 1022 patients with TNBC who underwent definitive breast surgery during 1999 to 2006 were identified from an institutional database. In total, 194 who had lymph node-negative tumors that measured 1 cm comprised the study population. Clinical data were abstracted, and survival outcomes were analyzed. RESULTS: The median follow-up was 73 months (range, 5-143 months). The median age at diagnosis was 55.5 years (range, 27-84 years). Tumor (T) classification was microscopic (T1mic) in 16 patients (8.2%), T1a in 49 patients (25.3%), and T1b in 129 patients (66.5%). Most tumors were poorly differentiated (n ¼ 142; 73%), lacked lymphovascular invasion (n ¼ 170; 87.6%), and were detected by screening (n ¼ 134; 69%). In total, 129 patients (66.5%) underwent breast-conserving surgery, and 65 patients (33.5%) underwent mastectomy. One hundred thirteen patients (58%) received adjuvant chemotherapy, and 123 patients (63%) received whole-breast radiation. The patients who received chemotherapy had more adverse clinical and disease features (younger age, T1b tumor, poor tumor grade; all P < .05). Results from testing for the breast cancer (BRCA) susceptibility gene were available for 49 women: 19 women had BRCA1 mutations, 7 women had BRCA2 mutations, and 23 women had no mutations. For the entire group, the 5-year local recurrence-free survival rate was 95%, and the 5-year distant metastasis-free survival rate was 95%. There was no difference between patients with T1mic/T1a tumors and patients with T1b tumors in the distant recurrence rate (94.5% vs 95.5%, respectively; P ¼ .81) or in the receipt of chemotherapy (95.9% vs 94.5%, respectively; P ¼ .63). CONCLUSIONS: Excellent 5-year locoregional and distant control rates were achievable in patients with TNBC who had tumors 1.0 cm, 58% of whom received chemotherapy. These results identified a group of patients with TNBC who had favorable outcomes after early detection and multimodality treatment. Cancer 2012;118:4944-52.

The present study suggests that neoadjuvant irradiation of cutaneous melanoma tumours prior to surgical resection can stimulate an endogenous anti-melanoma host immune response.