Early Multimodal Detection of Cancers Originating from Synthetic Hormonal Therapy in a p53 Knockout Murine Model
Prof Francois van der Westhuizen
Title of the project
Early multimodal detection of cancers originating from synthetic hormonal therapy in a p53 knockout murine model.
Estrogen has long been recognized as a carcinogenic agent that could increase the risk of developing various types of cancers. An increase in estrogen exposure has been associated with an increased risk to develop breast cancer, specifically. Estrogens metabolised through biotransformation reactions to catechol estrogens, may become highly reactive species if not further biotransformed, i.e. inactivated and subsequently excreted. These reactive molecules can then readily react with deoxyribonucleic acid (DNA) to form depurinating DNA adducts. Erroneous repair of the depurinated DNA can lead to the formation of mutations that may be involved in the initiation of certain cancers. The estrogens initiating this cancerous effect can come from various sources, including endogenous estrogen biosynthesis or exogenous estrogen exposure.
Some conditions that may alter the estrogen biotransformation homeostasis, include: early menstruation, late menopause, dietary exposure to estrogens (mycoestrogen found in fungi and phytoestrogens found in certain plants) and enterohepatic recirculation (gut microflora remove conjugated moieties from estrogens to convert estrogens back to its original active form). Additionally, estrogen intake from using combined oral contraceptives (COCs) or as hormonal therapy might also contribute to an imbalance in the normal estrogen metabolism and biotransformation.
Other studies have shown that the urinary estrogen profile of women might be indicative of their relative breast cancer risk. Analysis of natural urinary estrogens and estrogen metabolites in women will, therefore, be of great value to evaluate how different conditions (including COC use) affect the natural estrogen metabolism and biotransformation pathways, and thereby, also the activation of toxic metabolic pathways and the production of metabolites that may directly influence cancer risk.
Therefore, inexpensive and non-invasive methods for regular screening of these carcinogenic metabolites are needed and crucial for effective treatment. It could increase the likelihood of a more positive prognosis for the patient and limit the cost (and period) of treatment, or even lead to disease prevention.
In South Africa, many cancer patients go undiagnosed and untreated, resulting in premature and unnecessary deaths. This is in large part because they don’t have readily access to healthcare facilities in isolated rural, mostly poverty-stricken, communities. Instead, they have to rely on mobile laboratories or infrequent hospital and clinic visits to urban centers where long queues and poor service delivery discourages individuals from regular health screens. Additional contributing factors include the high cost of therapy, side-effects of chemotherapy, and cultural stigma. Our project aims to contribute to the development of a non-invasive, cost-effective, robust and rapid alternative approach for the early detection of estrogen-dependent cancer risk.
Value of the project in the struggle against cancer
The fight against cancer comprises different strategies that aim at i) early detection of the disease, ii) effective treatment of patients to inhibit or eradicate tumour growth and increase life expectancy or at least quality of life, or at iii) disease prevention through the promotion of healthier living conditions (e.g. through diet) and encouraging regular, early screening for tumorigenic biomarkers in order to detect potential cancer risk. Breast cancer is the most prevalent type of cancer among all women in South Africa and estrogen exposure has been identified as one of the risk factors for developing breast cancers.
Our study makes a significant contribution in the fight against cancer by providing an alternative screening method to detect estrogen-dependant cancer risk. The results from such a screening test may be used to design appropriate strategies to reduce this risk but may also motivate further tests and screenings in order to detect and diagnose cancer at a very early stage, which in turn may reduce treatment time and intensity and improve disease prognosis.
Furthermore, although sample analysis is still ongoing our results may also identify differences in the capacity to metabolise and detoxify hormone metabolites between black and white women in South Africa, which may in turn aid in developing tailored treatment/prevention strategies for women from different ethnic groups. This screening method also requires a less invasive sampling technique (urine instead of blood or a mammogram), which makes it more accessible for all women in South Africa.
Future plans for the project
This project certainly has a lot of potential for further study. One avenue would be to compare estrogen biotransformation capacity between different ethnic groups in South Africa and attempt to map any differences to specific polymorphisms or mutations that may affect this pathway and, thereby, predispose certain women to estrogen-induced cancer. Identification of effective treatment strategies to promote the effective detoxification of estrogen metabolites and minimize the formation of carcinogenic metabolites will also have to be investigated. Another question to be answered is whether estrogen metabolism is differentially involved in the formation of different types of breast cancer. Guided by the final results that will be obtained from the current study we, therefore, plan to apply for additional funding in 2020 to continue with the project and to investigate these questions. Also depending on the outcome of this study the research using mouse models, as initially planned, would also be a definite future prospect.