Targeting Cytochrome P450 Enzymes in Ovarian Cancers: New Approaches to Tumor-Selective Intervention.

Over the past decade, there have been significant developments in treatment for ovarian cancer, yet the lack of targeted therapy with few side effects still represents a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs and has a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial to understanding the pathophysiology of ovarian cancer since many isoforms are essential to the metabolism of xenobiotics and steroid hormones, which drive the disease's development. To the best of our knowledge, no review articles have documented the intratumoral expression of CYPs and their implications in ovarian cancer. Therefore, the purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with the effects of CYP polymorphisms on chemotherapy metabolism. Finally, we discuss opportunities to exploit metabolic CYP expression for the development of novel therapeutic methods to treat ovarian cancer.

Glypican-3 Differentiates Intraductal Carcinoma and Paget's Disease from Other Types of Breast Cancer.

Background and Objectives: breast cancer remains the most common health burden affecting females worldwide. Despite developments in breast cancer diagnostic approaches and treatment strategies, the clinical management of metastatic breast cancer remains challenging. Thus, there is a need to identify new biomarkers and novel drug targets for breast cancer diagnosis and therapy. Recently, aberrant glypican-3 (GPC3) expression in cancers has gained considerable interest in cancer research. The studies, however, have yielded contradictory results about GPC3 expression in breast cancer. Therefore, the current study aims to analyse GPC3 expression across a large panel of different breast cancer subtypes. Materials and Methods: GPC3 expression was immunohistochemically evaluated in 230 breast cancer patients along with eight normal tissues and its associations to clinical and demographic characteristics, as well as immunohistochemical biomarkers for breast cancer. Moreover, a public database consisting of breast cancer patients' survival data and GPC3 gene expression information was used to assess the prognostic value of GPC3 in the survival of breast cancer patients. Results: GPC3 expression was only characterised in 7.5% of different histological breast cancer subtypes. None of the normal breast tissues displayed GPC3 expression. Interestingly, all cases of Paget's disease, as well as 42.9% of intraductal and 16.7% of mucinous carcinomas were found to have GPC3 expression, where it was able to significantly discriminate Paget's disease and intraductal carcinoma from other breast cancer subtypes. Importantly, GPC3 expression was found more often in tumours that tested positive for the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), indicating more favourable histological subtypes of breast cancer. Consequently, longer relapse-free survival (RFS) was significantly correlated with higher GPC3 mRNA expression. Conclusions: Our study proposes that GPC3 is a promising breast cancer subtype-specific biomarker. Moreover, GPC3 may have the potential to be a molecular target for the development of new therapeutics for specific subtypes of breast cancer.

Cytochrome P450 1B1 Overexpression in Cervical Cancers: Cross-sectional Study.

BACKGROUND: Current standard treatments for patients with recurrent cervical cancer are not very effective and are associated with severe toxicity. Recently, the rational approach for the discovery of new therapies for cervical cancer is based on the alterations in the molecular biology of cancer cells. One of the emerging molecular changes in cancer cells is the aberrant expression of cytochrome P450 1B1 (CYP1B1). This unique enzyme has been reported to be selectively overexpressed in several cancers. OBJECTIVE: The aim of this study was to examine CYP1B1 expression in cervical cancers and to assess the enzyme's relationship with several clinicopathological features. METHODS: Immunohistochemistry was performed to examine CYP1B1 expression in 100 patient samples with cervical cancer and 10 patient samples with normal healthy cervical tissues. RESULTS: CYP1B1 was expressed in the majority of the cervical cancer samples (91/100, 91.0%) but not in normal healthy cervical samples. The difference in the expression of CYP1B1 between healthy and tumorous cervical tissues was significant (P=.01). Moreover, the frequency of CYP1B1 expression was found to be significantly higher in patients with advanced grades of the disease (P=.03) and in patients having metastasis to the lymph nodes (P=.01). Surprisingly, there was a significantly higher expression of CYP1B1 in patients with a high prevalence of human papilloma virus 16/18 (P=.04). CONCLUSIONS: The differential profile of CYP1B1 expression between cervical cancer tissues and normal cervical tissues suggests that CYP1B1 may be used as a target for future therapeutic exploitations.

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer.

BACKGROUND: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. METHODS: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme's relationship to several clinicopathological features and survival was explored. RESULTS: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p < 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p < 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p < 0.05). CONCLUSIONS: CYP4Z1 expression is associated with cervical cancer patients' survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.

Glypican-1 Overexpression in Different Types of Breast Cancers.

PURPOSE: Treatment of metastatic breast cancer patients is challenging and remains a major underlying cause of female mortality. Understanding molecular alterations in tumor development is critical to identify novel biomarkers and targets for cancer diagnosis and therapy. One of the aberrant cancer expressions gaining recent research interest is glypican-1. Several studies reported strong glypican-1 expression in various types of human cancers. However, none of these investigated glypican-1 expression in a large cohort of breast cancer histopathological subtypes. PATIENTS AND METHODS: Immunohistochemistry was used to assess glypican-1 expression in 220 breast cancer patients and its relation to demographic and clinical features, as well as important prognostic immunohistochemical markers for breast cancer. RESULTS: Intense glypican-1 expression was recognized in all breast cancer histopathological subtypes. Normal, healthy breast tissue displayed a heterogeneous low expression (20%). Importantly, a strong differential in glypican-1 expression was determined between normal and malignant breast tissues. Moreover, there was a significantly high rate of glypican-1 expression in advanced grades of breast cancer patients and larger tumor sizes. Unfortunately, the glypican-1 expression demonstrated no obvious relationship with the expression of various biomarkers in breast cancer. CONCLUSION: This study may establish glypican-1 as a promising new therapeutic target for the development of therapy in breast cancer.

Screening of Glypican-6 Expression in Benign, Primary and Metastatic Colon Cancers.

BACKGROUND: The development of colon cancer has been described as a multistep process of carcinogenesis. Understanding molecular and cellular changes underlying this process is required to determine potential biomarkers and therapeutic targets in colon cancers. Several molecular entities, including glypicans, are implicated in cancer development. Among these is glypican-6, which is overexpressed in a limited number of cancers. This study aims to characterise the glypican-6 expression in different types of colon cancer. METHODS: Immunohistochemistry was used to characterise glypican-6 expression in a panel of archived formalin-fixed, paraffin-embedded colon tissue types. These types included 39 normal colon tissues, 10 colon tubular adenomas, 60 colon adenocarcinomas without metastasis and 60 colon adenocarcinomas with metastasis. Glypican-6 expression relation to demographic and clinicopathologic features was also examined. RESULTS: Glypican-6 was strongly expressed in benign, primary and metastatic colon tumours. Normal tissue samples exhibited low to undetectable levels of glypican-6. A significantly high glypican-6 expression was displayed in colon cancers with lymph node metastasis, high depth of invasion, distant metastasis, high histological grades and late stages of the disease (P < 0.05). Importantly, a significant differential in glypican-6 expression was found between normal tissues and different types of colon cancer tissues. Moreover, the highest glypican-6 expression was more frequently found in metastatic tumours, followed by primary tumours and the least in benign tumours (P < 0.05). CONCLUSIONS: Selective expression of glypican-6 may establish a basis for potential use as a tissue biomarker or as a novel therapeutic target in treatment of colon cancer.