PhD Defence by Jacob Ardenkjær-Skinnerup

Principal supervisor:

• Senior Researcher Gitte Ravn-Haren

Co-supervisors:

• Professor Ulla Vogel
• Senior Researcher Niels Hadrup

Examiners:

• Senior Researcher Hanna K. L. Johansson, DTU Food
• Professor Sari Mäkelä, University of Turku
• Associate Professor Jakob B. Hansen, University of Copenhagen

Chairperson at defence:

• Senior Adviser Kirsten Pilegaard

Resume
Peroxisome proliferator-activated receptor gamma (PPARγ) is a protein abundant in fat tissue where it plays a role in fat cell development and hormonal regulation. The function of PPARγ can be modified by environmental and occupational chemicals, such as alcohol, which can lead to disruption of the hormonal balance. A high level of the hormone estrogen is a risk factor for breast cancer. PPARγ has been shown to limit the production of estrogen by restricting the expression of the estrogen-producing enzyme, aromatase. The focus of this project was to study how chemical exposure can impact breast cancer development by elevating estrogen production via inhibition of PPARγ.

Chemical inhibitors of PPARγ have been studied extensively, but experimental results are often inconsistent. Therefore, a selection of previously identified PPARγ inhibitors were confirmed by analyzing their effects on PPARγ activity. It was also found that these chemicals can block fat cell development. This led to a higher aromatase level because fat precursor cells express more aromatase than fully developed fat cells. In addition, exposure to PPARγ inhibitors could increase aromatase expression in fat cells that were already fully developed. Thus, two different mechanisms through which PPARγ may increase estrogen production were identified.

It can be concluded that PPARγ inhibitors are likely to act as breast carcinogens, since they can increase the expression of the estrogen-producing enzyme, aromatase, in the fat tissue. This project has contributed to a better understanding of the mechanisms potentially leading to breast cancer. However, further studies are important to get further insights into potential health risks presented by various environmental and occupational exposures.