Development of an Alternative Method for Testing the Carcinogenic Potential of Hormone-active Substances

Breast cancer is the most common cause of cancer death in women worldwide and, together with colorectal cancer, is one of the two most common cancers in Germany. In order to uncover potential risk factors and to decipher the underlying molecular mechanisms, a large number of animal experiments are performed. Ethical aspects and limitations of animal models in transferability to humans make alternative methods increasingly necessary also in this research field.

The aim of this project is to develop novel in vitro alternative and complementary methods to animal testing for breast and colorectal cancer research by using cell culture-based methods of basic biomedical research. The Bf3Rs research focuses on a group of substances with hormone or hormone-like effects, which we encounter naturally, but which are also present in biocides, pesticides or even as a component in plastic packaging. These substances, also known as endocrine active substances, can not only influence the hormone system, but can also promote the development and progression of  cancer, for example by interfering with cell division processes or by stimulating the metastatic dissemination of cancer cells. The underlying cellular and molecular mechanisms of these hormone-triggered cancer-prone lesions remain poorly understood, but their identification is a prerequisite for the development of alternative methods to animal testing. Hence, the Bf3Rs research intends to identify and to characterize a potential link between hormones, defects during cell division and the development of breast and colorectal cancer. In addition, the Bf3R develops novel in vitro alternative and complementary methods for breast and colorectal cancer research based on mechanistic insights of biomedical research.

Using a broad spectrum of molecular and cell biological methods and employing state-of-the-art high-resolution microscopy techniques, we are working on the following key areas:

• Characterization of cell division defects induced by endocrine active substances
• Structural and interaction analyses at the single molecule level using the super resolution PALM (Photo-Activated Localization Microscopy) technology
• Investigation of the potential of endocrine active substances to promote the development and progression of breast or colorectal cancer
• Uncovering relevant intracellular signaling pathways and target proteins
• Development of a high-throughput / high-content screening to identify endocrine active substances with carcinogenic properties

Persistent chromosomal maldistribution during cell division, called whole chromosomal instability (w-CIN), is a major feature of cancer cells. The presence of multiple centrosomes are associated with spindle geometry and chromosome alignment defects, which promote defective attachments of chromosomes to the mitotic spindle (lagging chromosomes) and subsequently lead to w-CIN and aneuploidy. Endocrine active substances may have the potential to trigger these key cancer-associated lesions by binding to estrogen receptors, thereby promoting breast and colon carcinogenesis.