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: Hematology, Oncology
• Term: from 2011 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194083719

Overexpression of ER alpha is found in around 70% of all human breast carcinomas whereas in normal breast tissue, ER alpha+ cells are in the minority. Besides regulating proliferation, survival and differentiation of normal breast tissue, ER alpha plays an important role in the tumorigenesis of breast tumors. Loss of tumor suppressors that lead to inadequate ER alpha expression and function is therefore considered to be one of the most important initial events during breast cancer development. During the first funding period I have shown that RASSF1A inhibits the expression of the ER alpha gene and inhibits ER alpha activity. Furthermore I have demonstrated that the RASSF1A-mediated inhibition of ER alpha expression is Akt dependent. In a first step RASSF1A cause inhibition of Akt and in turn activation of FOXO3A. In the following activated FOXO3A might inhibit ER alpha gene expression. During the second funding period I will reveal the complete mechanism by which RASSF1A inhibits ER alpha gene expression. Therefore I will additionally prove a potential inhibitory function of RASSF1A upon the NF-kB signalling pathway and its relevance for ER alpha gene expression. During the first funding period I have started in vivo experiments based on Rassf1a-/- mice. Aim of these experiments is to investigate a potential inhibitory influence of RASSF1A upon estrogen-mediated breast cancer initiation and progression. These experiments should be finished during the second funding period. Additionally I will investigate a potential inhibitory function of RASSF1A upon initiation and progression of progestin-driven breast cancerogenesis in vivo. Furthermore I will investigate whether RASSF1A and Caveolin-1 might act in concert to inhibit ER alpha expression and function, as well as signalling pathways that are important for breast epithelial cell transformation and malignant progression.

• DFG Programme: Research Grants
• Participating Persons: Dr. Cristina Cotarello; Professor Charles James Kirkpatrick, Ph.D.; Dr. Arno Schad; Professor Dr. Marcus Schmidt