The Differential Regulation of Human Telomerase Reverse Transcriptase and Vascular Endothelial Growth Factor May Contribute to the Clinically More Aggressive Behavior of P63-Positive Breast Carcinomas

Abstract

p63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.

Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation

“…In agreement, the combined single-allelic loss of p63 together with p53 results in higher metastasis occurrence compared with p53 heterozygous mice, and knockdown of DNp63a in squamous cell lines leads to increased migratory and invasive behavior (Barbieri et al, 2006). In breast cancer, however, the situation seems to be more complex, as both a positive and negative correlation between p63 and metastasis have been reported (Adorno et al, 2009;Garcia et al, 2007;Ribeiro-Silva et al, 2005). In addition, DNp63a expression levels in head and neck squamous cell carcinomas are shown to correlate with a positive clinical outcome to chemotherapeutic treatment, such as cisplatin (Zangen et al, 2005).…”

Identification and differential expression of human carcinoma-associated antigens in hepatocellular carcinoma tissues

“…CLIMP63 expression also correlated with advanced pathological stage, tumor size and the expression of human telomerase reverse transcriptase, tissue inhibitor of matrix metalloproteinase 1 and vascular endothelial growth factor. 24 In addition, tissue plasminogen activator (tPA) binding to CLIMP63 on the plasma membrane regulates the response of vascular smooth muscle cells to a variety of blood vessel injuries. This is in accordance with the function of HCA suppressing E-cadherin cell adhesion.…”

Letter to the Editor

“…In a recent work, my colleagues and I studied the relationship between p63 expression and several key regulators of the cell cycle in breast carcinomas, and we did not find a statistical significance between p63 and epidermal growth factor receptor (EGFR) status. 6 The data from the Bossuyt paper make this finding very interesting because the high expression of EGFR found in breast carcinomas with squamous differentiation may suggest that the molecular biology of p63positive breast carcinomas is not related to squamous differentiation. However, this assertion is speculative and has to be tested.…”