Dorraya El-Ashry, Ph.D.
Associate Professor of Medicine
Description of Research
Breast cancer presents as either estrogen receptor alpha-positive (ERalpha+) or alpha–negative (ERalpha-), and the presence of ERalpha correlates with a better prognosis and response to hormonal therapy while the absence of ERalpha correlates with more aggressive and metastatic phenotypes, no response to hormonal therapies, and overexpression of growth factor receptors (GFRs) such as EGFR or c-erbB-2. Dr. El-Ashry's laboratory focuses on understanding the interaction between ERalpha signaling and GFR signaling in breast cancer progression. Using cell line models developed by her lab, scientists discovered that the overexpression of c-erbB-2 or EGFR directly induces the ERalpha- phenotype via the resultant hyperactivation of MAPK. Importantly, this MAPK induced down-regulation of ERalpha is reversible via abrogation of MAPK activity. Using genomic approaches, scientists were able to ascribe a major role for upregulation of MAPK activity in the biology of ERalpha- breast cancer and have identified specific MAPK substrates that are important for this biology. In addition, the lab also is establishing key EGFR and c-erbB-2 signaling substrates specifically in breast cancer cells as this is important for investigating interactions between ERalpha and GFR signaling pathways that may be responsible for initiating the generation of tumor cells that are either ERalpha+ or ERalpha-. The lab's cell line models are ideal to determine why high expression of ERalpha and EGFR/c-erbB-2 are mutually exclusive in breast cancer and thus the mechanisms that underlie the generation of the ERalpha+ versus ERalpha- phenotype. Most exciting is the very recent finding that inhibition of MAPK in primary cultures and explants from ERalpha- breast tumors can result in re-expression of ERalpha in a significant subset of specimens. Importantly, scientists have recently demonstrated that the re-expression of ERalpha in ERalpha- breast cancer cell lines and tumor cells via inhibition of MAPK activity was able to restore anti-estrogen sensitivity. These findings have tremendous implications for future therapeutics. Translating these laboratory studies to patient practice has the potential of being one of the most significant advances in breast cancer treatment for ERalpha- breast cancer.
Selected Cancer-Related Publications
- Brinkman JA, El-Ashry D. ER re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers. J Mammary Gland Biol Neoplasia 14:67-78, 2009. Read more »