Poly(ADP‐ribose) polymerase‐1, a novel partner of progesterone receptors in endometrial cancer and its precursors

Abstract

Endometrial carcinomas are the most common malignancy of the female genital tract. Although the downregulation of the progesterone receptor (PR) in the progression of endometrioid carcinomas (ECs) has been well documented, the mechanism of PR alteration in endometrioid carcinogenesis is poorly understood. Recently, biochemical studies have shown that the DNA strand break-sensing molecule poly-(ADP-ribose) polymerase (PARP-1) was associated with the DNA binding domain of PR. In our present study, we show that in normal endometrial epithelium, the expression level of PARP-1 protein is high in the proliferative phase but markedly decreases during the secretory phase. Interestingly, PARP-1 expression gradually increases in nonatypical and atypical endometrial hyperplasia, reaching its highest level in grade I, and decreases significantly toward grade III ECs. Endometrial carcinomas (ECs) are the most common malignancy of the female genital tract, and 97% of all uterine corpus cancers are endometrial carcinomas. 1 Approximately 23% of women with endometrial hyperplasia progress to adenocarcinoma. 2 A progression of cellular atypia is observed in uterine lesions, ranging from glandular-cystic endometrial hyperplasia, atypical hyperplasia and well-differentiated uterine adenocarcinoma to less well-differentiated uterine neoplasia, and the most likely precursor lesion of invasive carcinoma is identified as atypical hyperplasia. 3 Although there is little doubt that atypical hyperplasia is a marker for an increased risk of adenocarcinoma development, the aetiology of endometrial cancer and the molecular mechanisms of its evolution from preneoplastic lesions to malignancy, as well as the factors that lead to invasive carcinoma, have not been well defined. The proliferation and the differentiation of the endometrium are influenced by steroid hormones, estrogen and progesterone through their nuclear receptor signaling pathways. Progesterone receptors (PRs) are ligand-activated nuclear transcription factors that are involved in the development and the terminal differentiation of female target tissues, such as endometrium tissues. They bind specifically to DNA at progesterone response elements through a DNA binding domain. 4 High levels of PR are associated with better, disease-free survival of endometrioid carcinoma (EC). 5 Until now the most powerful predictive and prognostic factors were linked to the steroid receptor signaling pathway.In line with the function of PR, biochemical studies showed that Poly(ADP-ribose) polymerase (PARP-1) regulates the transcriptional activities of steroid receptors. 6 Interestingly, PARP-1 has been shown to associate with the DNA binding domain of PR. 7 Accumulating evidence showed that PARP-1 or its activity is required for transcriptional regulation of several genes involved in cell cycle control and cell proliferation/differentiation. 8 PARP-1 (EC2.4.2.30) is a nuclear enzyme that catalyzes the poly(ADPribosyl)ation of target proteins and has been proposed to play a role in DNA repair...

PARP1 Is Overexpressed in Nasopharyngeal Carcinoma and Its Inhibition Enhances Radiotherapy

“…Consistent with our observations, overexpression of PARP1 has also been reported in other tumors, including colorectal cancer (26), endometrial cancer (27), hepatocellular carcinoma (28), and melanomas (27). Several studies have reported the association of PARP1 protein expression with a worse prognosis.…”

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

“…More recently, Carbone et al (2008) showed that PARP-1 activity was induced by mitogen stimulation and contributed to the G0 -G1 cell-cycle transition by the induction of immediate-early genes such as cMyc and c-Fos. Another study revealed that PARP-1 expression gradually increases in nonatypical and atypical endometrial hyperplasia compared with normal endometrial epithelium (Ghabreau et al, 2004). Published data indicate that increased proliferation is a major determinant of PARP-1 expression and activity.…”

Genetic polymorphisms in DNA base‐excision repair genes ADPRT, XRCC1, and APE1 and the risk of squamous cell carcinoma of the head and neck

“…Moreover, it is possible that effect of the ADPRT variant genotypes may be tissue-specific. Indeed, studies have indicated that ADPRT expression levels appear to be low in breast cancer 30 but high in endometrial cancer, 31 indicating ADPRT may play different roles in different types of tumors.…”