Divergent ERα co-factor landscapes in gynecological cancers: implications for disease progression and therapy

Estrogen receptor alpha (ERα) is an established biomarker for breast tumors, the loss of which is associated with poor cancer progression. Over 70% of breast cancers express ERα and targeting this protein has helped stem the progress of breast cancer. Therefore, it is paradoxical that only a small fraction of patients with ovarian and uterine cancers, which express ERα, are insensitive to antiestrogenic therapies. We propose the hypothesis that ERα association with different cofactors dictates the susceptibility of these cancers to therapies. To support this hypothesis, we analyzed data from cBioportal patient samples and showed that a strong positive correlation exists between ERα and its cofactors GATA3 and FOXA1 in breast cancer, but not in ovarian and uterine cancers. We further show that ERα genomic localization differs in the three cancer types, using available ChIP-seq datasets. Together, our analyses suggest that both localization and the nature of co-factors might be relevant for driving ERα-dependent cancer progression in different cell environments. We further discuss potential mechanisms for these differences in this commentary.