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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Epigenetic Control of Obesity-induced Tumor Initiation in Breast Cancer

Alternative title: Epigenetisk kontroll av fedme-indusert tumorinitiering i brystkreft

Awarded: NOK 9.6 mill.

Being obese increases our risk of developing 13 types of cancer – these are cancers that non-obese individuals may not develop. Consequently, being obese is estimated to be the underlying reason for about 500 000 cancer cases each year. This project aims to find out why. And further, if we can determine how obesity links to cancer risk, can we possibly find ways to prevent this? Cancers are typically associated with mutations in our DNA. Thus far, we have not been able to detect any mutational differences between obese and non-obese patients. Instead, we have found large changes in the organization of the DNA – a process known as epigenetic regulation. Epigenetic regulation of the DNA controls what part of the DNA can be used by the cell and which parts cannot. We have found that cancers that grow in obese individuals have vastly changed epigenetic control of the DNA. And that this, again controls the ability to form a tumor. In this proposal, we will dig deeper into why being obese has such a profound effect on tumor fates.

Today, we know that obesity increases the risk of developing thirteen types of cancers. Thirteen cancer types that normal-weight individuals may not develop although they carry the same cancer risk loci as obese individuals. Despite the massive implications of such linkage for prevention and therapy, efforts to delineate such mechanisms have so far been hampered by the high complexity and systemic character of both obesity and cancer formation. My laboratory has demonstrated that cancer cells undergo adaptive epigenetic remodeling and gain tumor initiating properties when exposed to prolonged periods of obesity conditions. The major outstanding research question is: How does adaptation to the obese state cause specific changes in chromatin? Our central hypothesis is that the distorted metabolic environment in obese breast cancer patients engenders epigenetic deregulation leading to alterations in the chromatin structure and consequently transcriptional reprogramming towards tumor-initiating cancer cell phenotypes. We will address this hypothesis by measuring how obesity-induced dysregulation of cellular metabolites affects tumour metabolism and how such changes regulate tumor initiation capacity (WP1). We will investigate the specific epigenetic modifications impacted by the obese environment (WP2) and the reader and writer enzymes required for this adaptation (WP3).

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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