The majority of breast tumors are estrogen receptor α (ER) positive. Hormonal adjuvant therapy using tamoxifen (OH-Tam) or aromatase inhibitors (AIs) are the mainstay in the treatment of ER+ breast cancer. However, resistance mechanisms develop during either hormone depletion or OH-Tam adjuvant therapy. The mechanistic events underlying the progression to emergence of drug resistance are poorly understood.
Hormonal adjuvant therapies are overall tumoristatic. In hormone-depleted MCF-7 breast cancer cells, ligand-independent actions of ER supported a basal fraction of S-phase cells through maintenance of the basal expression of the retinoic acid receptor α1 (RARα1). The apo-ER/apo-RAR α1 axis regulated a set of genes that were both OH-Tam insensitive and all-trans retinoic acid (ATRA)-insensitive. The target genes that were activated by this axis predominantly promote cell cycle progression and mitosis whereas the target genes repressed through the axis are predominantly negative regulators of the cell cycle and mitosis. RARα1 was the only RARα isoform expressed in MCF-7 cells and most breast tumors and since this RAR subtype is known to be genetically redundant; we therefore propose that targeted inactivation or downregulation of RARα1 may improve hormonal adjuvant therapies by significantly reducing the ability of hormone-sensitive breast cancer cells to maintain a basal level of proliferation under conditions of hormone-depletion or OH-Tam treatment with minimal side effects on non-target tissues.
Another aspect of ER action that has been remarkably under-investigated is gene repression. E2 directly and indirectly represses more genes than it activates and in the majority of those genes, hormonal adjuvants partially or fully block the repression. Using the folate receptor α gene promoter as a model, we established a novel non-classical mechanism for direct gene repression by E2 in which ER forms a TAFII30-associated co-repressor complex; OH-Tam prevents this repression by simply dissociating the complex. Comprehensive ontology analysis of the subset of OH-Tam sensitive genes repressed by E2 revealed predominant associations with physiological functions that support an aggressive tumor phenotype correlated with poor prognosis. Hormonal adjuvant treatments may prevent this repression and encourage aggressive phenotypes in tumors cells that have acquired hormone-insensitivity for growth.