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Title: Role of IL-6 and ERα in the genotoxicity of environmental carcinogens in mammary cells
Author: Malik, Durre-
ISNI:       0000 0004 7427 686X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Worldwide, breast cancer is the most commonly diagnosed cancer in women. Inherited genes (15%) have a role in the prevalence of breast cancer while diet and lifestyle play major roles (around 85%). Environmental factors such as consumption of red or processed meat, cigarette smoke and inflammation are major risk factors of this disease. Despite the known breast cancer risk factors, the underlying mechanisms are not yet well studied. Benzo(a)pyrene B(a)P and PhIP (2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine) are among the most abundant procarcinogens present in cooked and processed meat and are linked with the incidence of breast cancer. Upregulation of cytochrome P450 (CYP450) enzymes that activate these procarcinogens leading to increased DNA damage has been observed in breast cells. Interleukin-6 (IL-6) is one of the most stable inflammatory biomarkers upregulated in breast cancer and linked with the poor prognosis of breast cancer. IL-6 plays a key role in tumour progression through tumour-promoting signaling pathways and epigenetic gene regulation. I hypothesized that IL-6 can regulate CYP enzymes that can modulate the genotoxicity of procarcinogens. This hypothesis was investigated by mechanistic studies in in-vitro cell culture. Increase in the genotoxicity of pro-carcinogens via CYP regulation was observed in the presence of IL-6 in breast cells. Moreover, I investigated the role of Estrogen receptor in the genotoxicity and generation of oxidative stress by PhIP. Hormone responsive breast tumours are among the most fatal and widespread of cancer types and estrogens are well-known to increase tumourigenesis. PhIP is known to exhibit powerful estrogenic activities. The presence of estrogen receptor (ER) can increase the susceptibly of cells to oxidative stress that can play a vital role in tumour initiation and progression. I therefore hypothesized that the presence of a functional ER receptor can increase PhIP genotoxicity and ability to generate oxidative stress. This hypothesis was tested using in-vitro techniques in ER positive MCF-7 and ER negative MDA-MB-231 cells. Increased genotoxicity and oxidative stress via CYP regulation was observed in MCF-7 compared to MDA-MB-231 cells following PhIP treatments. Interestingly, I also found PhIP can augment the potential of ethanol to generate oxidative stress via CYP regulation leading to increase in DNA damage. Ethanol is one of the most important modifiable risk factors of breast cancer. Lastly, I investigated if B(a)P can independently induce the production of inflammatory cytokines, leading to increased migration and invasion in breast cancer cells. Increase in the production of inflammatory mediators, migration and invasion of breast cells following B(a)P treatments was observed in MCF-7 and MDA-MB-231 cells. Induction of IL-6 by B(a)P leading to deregulation of miRNAs, that can regulate the metastatic potential of breast cells was also observed. This shows that B(a)P can initiate tumours not only via genotoxicity but also by non-genotoxic epigenetic events. Overall, this thesis suggests novel genetic and epigenetic mechanisms by which procarcinogens can initiate and potentiate tumourigenesis.
Supervisor: Gooderham, Nigel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral