Characterization of RASSF1A as a potential regulator of the estrogen receptor alpha in normal mammary epithelia and its implication in breast cancer development

• Applicant: Professorin Dr. Sonja Thaler
• Subject Area: Gynaecology and Obstetrics ; Cell Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388989224

Overexpression of the estrogen receptor alpha (ER alpha) is found in around 70% of all human breast carcinomas, whereas in normal breast tissue ER alpha positive cells are in the minority. Besides regulating proliferation, survival and differentiation of normal breast tissue, the ER alpha plays an important role in breast tumorigenesis. Loss of tumor suppressors that regulate ER alpha expression and function is therefore considered to be one of the most important initial events during breast cancer development. During the previous funding periods, I have shown that RASSF1A inhibits the expression of the ER alpha gene and inhibits ER alpha activity. Furthermore, I have demonstrated that RASSF1A mediates inhibition of ER alpha expression through a complex, hierarchically-organized network that includes the proteins YAP1, Akt, FOXO3A and FOXM1. Additionally, I have demonstrated that RASSF1A efficiently inhibits the ER alpha-mediated outgrowth of breast cancer cells. Furthermore, I have shown that within breast cancer cells RASSF1A not only inhibits ER alpha but also other proteins and signaling pathways that mediate resistance towards ER alpha-inhibitory drugs. Therefore, during the next funding period I plan to investigate whether substances that either imitate the function of RASSF1A or reactivate RASSF1A expression could improve the treatment of ER alpha+ and therapy-resistant breast cancer. To this end I will perform a variety of in vitro and in vivo experiments using primary mammary carcinoma cells from therapy-resistant breast cancer patients. During the previous funding periods, I was also able to demonstrate an inhibitory influence of RASSF1A on the growth of luminal breast tumors using in vivo experiments based on the Rassf1a-/- mouse. These results show that RASSF1A is an important regulator of ER alpha and that the loss of RASSF1A promotes the development of ER alpha+ breast carcinomas. In addition, using the Rassf1a-/- mouse, I have begun to mechanistically investigate the inhibitory effect of RASSF1A on the initiation of breast tumorigenesis. These experiments will be continued and completed during the coming funding period. In addition, I aim to use the Rassf1a-/- mouse to investigate whether the loss of RASSF1A leads to increased inflammatory processes and whether these inflammatory processes have a promoting effect on breast tumorigenesis.

• DFG Programme: Research Grants