Understanding the Tumor Suppressive Functions of Estrogen Receptor β in Breast Cancer
Bado, Igor Landry 1986-
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Breast cancer is a heterogeneous disease with regard to clinical outcome and molecular characteristics. Some breast cancers are more aggressive because they express mutant proteins with potent oncogenic functions including mutant p53 proteins with gain of functions. Such tumors are often resistant to therapies. Accumulating data show positive correlations between ERβ1 and better survival, indicating more important roles of the receptor in breast cancer. First, we investigated the role of ERβ in triple negative breast cancer cells (TNBCs) that are mutant for p53. These cells are derived from very aggressive cancers with highly metastatic and chemoresistant properties. TNBC are negative for ERα, PR, and Her2, and there is no effective targeted therapy. Despite the lack of ERα, a significant number of TNBCs express ERβ. ERβ1 displays anti-migratory, anti-invasive, and anti-metastatic properties. However, the mechanism underlying its function is not well understood. Using molecular technics, we found that ERβ1 opposes mutant p53 gain-of-function through direct interaction. Most importantly, we found that ERβ1 can use mutant p53 as a co-factor to alter gene transcription. Further, the ERβ1-induced epithelial transformation was p63-dependent, suggesting an association between ERβ1, mutant p53 and p63. Second, we investigated the role of ERβ in ERα-positive breast cancer cells. These cells are derived from less aggressive tumors that respond better to hormonal therapy. ERα-positive breast cancers often express wild-type p53, yet p53 tumor suppressive function is inactivated. Several factors including ERα have been found to inhibit wild-type p53 activity. Previous studies have shown anti-proliferative responses following upregulation of ERβ1 in ERα-positive breast cancer cells. ERβ1 was also shown to correlate with better overall and disease-free survival in patients with ERα-positive breast cancer especially after hormonal therapy. Still, the mechanism through which ERβ1 associates with improved prognosis had yet to be investigated. We show that ERβ1 enhances wild-type p53 activity in ERα-positive cells. Further, we found that ERβ1-specific ligands can affect p53 transcriptional activity. Overall, we were able to suggest some novel mechanisms through which ERβ1 elicits its tumor suppressive function and propose ERβ1 as a potential good marker and target for breast cancer treatment.
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