High-risk human papillomaviruses (HPVs) could be important risk factors for breast carcinogenesis and metastasis. Based on this hypothesis, we recently studied the effect of E6/E7 onco-proteins of high-risk HPV type 16 in two non-invasive human breast cancer cell lines, BT20 and MCF7; we reported that E6/E7 converts these cell lines to invasive cells. This is accompanied by an overexpression of Id-1, which is an important regulator of breast metastasis. In this investigation, we examined the presence of highrisk HPVs (16, 18, 31, 33 and 35) and the expression of their E6 onco-protein as well as their correlation with Id-1 gene expression, using polymerase chain reaction (PCR) and tissue microarray (TMA) analysis, respectively, in a cohort of 113 Syrian breast cancer patients. We found that high-risk HPV types 16, 18, 31, 33 and 35 are present in 8.84, 9.73, 7.07, 55.75 and 37.16% of our samples, respectively, which represent invasive breast cancers. Overall, 69 (61.06%) of the 113 samples are HPV positive; among these specimens 24 tissues (34.78%) are coinfected with more than one HPV type. Furthermore, we report that the expression of the E6 onco-protein of these high-risk HPVs is correlated with Id-1 overexpression in the majority of invasive breast cancer tissue samples. Our data suggest that high-risk HPV infections are associated with human breast cancer progression in Syrian women.

Epstein–Barr virus (EBV) has been recently shown to be co-present with high-risk human papillomaviruses (HPVs) in human cervical cancer; thus, these oncoviruses play an important role in the initiation and/or progression of this cancer. Accordingly, our group has recently viewed the presence and genotyping distribution of high-risk HPVs in cervical cancer in Syrian women; our data pointed out that HPVs are present in 42/44 samples (95%). Herein, we aim to explore the co-prevalence of EBV and high-risk HPVs in 44 cervical cancer tissues from Syrian women using polymerase chain reaction, immunohistochemistry, and tissue microarray analyses. We found that EBV and high-risk HPVs are co-present in 15/44 (34%) of the samples. However, none of the samples was exclusively EBV-positive. Additionally, we report that the co-expression of LMP1 and E6 genes of EBV and high-risk HPVs, respectively, is associated with poorly differentiated squamous cell carcinomas phenotype; this is accompanied by a strong and diffuse overexpression of Id-1 (93% positivity), which is an important regulator of cell invasion and metastasis. These data imply that EBV and HPVs are co-present in cervical cancer samples in the Middle East area including Syria and their co-presence is associated with a more aggressive cancer phenotype. Future investigations are needed to elucidate the exact role of EBV and HPVs cooperation in cervical carcinogenesis.

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The association between polymorphisms in the p53 tumor suppressor gene and breast cancer risk has been studied in many human populations with conflicting conclusions. However, similar studies in Arab women are not available, and the status of these polymorphisms in this ethnic population is not known. We investigated the status of four known p53 gene polymorphisms and their possible role in breast cancer risk in Arab women. Genotyping was performed for 288 breast cancer women and 188 controls to determine Pro47Ser, Arg72Pro, Intron 3 Ins16 bp and intron 6 (G > C) polymorphisms. The p53 variant Pro47Ser was detected only in one Kuwaiti breast cancer patient and was not detected in any of the control subjects. Frequency of Arg/Arg at codon 72 was 26.6% in controls and 28.1% in patients, Arg/Pro frequency was 59.6% in controls and 69.4% in patients, the Pro/Pro genotype was 13.8% in controls and 2.4% in patients. We observed that women with Pro/Pro genotype have decreased risk for developing breast cancer (OR=0.166, 95% CI=0.067-0.411, p<0.001). The intron 3 genotypes were A1/A1 (48.9%), A1/A2 (40.6%) and A2/A2 (10.5%) in controls and A1/A1(42.4%), A1/A2 (52.8%) and A2/A2 (4.8%) in cases. The intron 6 genotypes were 92.4% (GG), 7.6% (GC) and 0% (CC) in controls and 96.5% (GG), 3.5% (GC) and 0% (CC) in cases. No statistically significant differences between patients and controls were observed for intron 3 and intron 6 polymorphisms. Our data show that proline homozygosity at p53 codon 72 is associated with decreased breast cancer risk in Arab women.

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...

Infection by high-risk human papillomaviruses (HPVs) is considered to be the central cause of invasive cervical cancer. Previously reported studies have shown that Id genes regulate cell invasion and metastasis in several human carcinomas including cervical cancer. In order to investigate the correlation between high-risk HPVs and Id genes in human cervical cancer, the presence of high-risk HPVs and their association with Id gene expression was examined using PCR methods and tissue microarray analyses in a cohort of 44 cervical cancer patients from Syria. This study showed that high-risk HPVs were present in 42 samples (95%) that represent invasive cervical cancers and that the most frequent high-risk HPV types in Syrian women were 33, 16, 18, 45, 52, 58, 35, 51 and 31. Furthermore, the expression of E6 oncoprotein of high-risk HPVs was found to correlate with overexpression of Id-1, but not of Id-2, Id-3 or Id-4 in the majority of invasive cervical cancer tissue samples. These data suggest that high-risk HPVs can enhance the progression of human cervical cancer through Id-1 regulation.

Endometrial carcinomas are the most common malignancy of the female genital tract and the third most common cancer in women. Progesterone and oestrogen receptors (PRs, ERs) are the most widely documented prognostic and predictive factors in endometrioid adenocarcinoma. Besides the hormonal pathway involved in the progression of preneoplastic and neoplastic lesions, alterations of the DNA methylation status have been shown to be an early signal of tumorigenesis. In this study, we show that in normal endometrium, during the proliferative phase, DNA methylation and PR expression are high, with a significant decline towards the end of the secretory phase and a gradual increase in non-atypical and atypical endometrial hyperplasia; they reach their highest level in grade I, then decrease significantly in grade-II and grade-III endometrioid adenocarcinomas. During each stage, a significant positive correlation is observed between DNA methylation and PR (P<0.0001). The strong parallelism between DNA methylation and PR expression precludes establishing a precise determination regarding the timing of these events, clearly involved in the genesis of endometrioid adenocarcinoma.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection; persistent infection with high-risk types of HPV present a major risk factor for the initiation and progression of a variety of human carcinomas including cervical, colorectal, head, and neck (HN) as well as breast carcinomas. A huge number of studies investigated and reported the incidence of high-risk HPVs in these cancers worldwide particularly in the developed countries; therefore, two HPV prophylactic vaccines against the two most frequent high-risk HPV types (16 and 18) have been developed and used worldwide. However, there are very limited studies about the prevalence of HPVs in the developing countries especially in Africa and some states of the Middle East. In this mini review, we outline the presence of high-risk HPVs in human cervical, colorectal, HN as well as breast cancers in the Syrian population, which was recently explored for the first time by a Canadian/Syrian group.