The role of xenoestrogens and GPER receptor for centrosome amplification and chromosomal instability in colorectal cancer cells

• Applicant: Dr. Aline Katharina Stolz-Ertych
• Subject Area: Toxicology, Laboratory Medicine ; Endocrinology, Diabetology, Metabolism ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465732234

Orally ingested endocrine active substances (EAS) get in direct contact with the intestinal mucosa and thus, increase the risk for toxic effects on intestinal cells, such as cellular transformation, migration and invasion. Recent work suggests a link between synthetic EAS with estrogenic activity (so-called xenoestrogens) and increased risk of colorectal cancer, by affecting cell division processes and stimulating colon cancer-associated processes such as cell proliferation, migration and metastasis. However, the underlying mechanisms of this xenoestrogen-induced risk potential are still unclear and will therefore be focus of the proposed project. Our preliminary results assigned naturally estrogens and xenoestrogens a pivotal role in centrosome amplification and whole chromosome instability (w-CIN), which are both hallmarks of colon carcinogenicity and threaten genome stability. Interestingly, these colon cancer-prone phenotypes seem to depend on the alternate estrogen receptor GPER and most likely on GPER-mediated regulation of centrosomal kinases upon xenoestrogen-treatment. Following these findings, we now aim to deepen a xenoestrogen/GPER/ centrosome-axis that regulates centrosome function and chromosome stability in colon (cancer) cells and identify further centrosome candidates regulated by this pathway. Doing so, we will i) uncover the mechanisms and cellular consequences of (xeno)estrogen-triggered centrosome amplification in colon (cancer) cells, ii) identify novel centrosome targets (cTGs) regulated by a xenoestrogen/GPER-axis, and iii) characterize the impact of the xenoestrogen/GPER/cTG-axis on the regulation of centrosome numbers and chromosome stability.

• DFG Programme: Research Grants