Disruption of estrogen receptor beta's DNA binding domain impairs its tumor suppressive effects in triple negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive sub-type of the disease which accounts for a disproportionately high percentage of breast cancer morbidities and mortalities. For these reasons, a better understanding of TNBC biology is required and the development of novel therapeutic approaches are critically needed. Estrogen receptor beta (ER beta) is a reported tumor suppressor that is expressed in approximately 20% of primary TNBC tumors, where it is associated with favorable prognostic features and patient outcomes. Previous studies have shown that ER beta mediates the assembly of co-repressor complexes on DNA to inhibit the expression of multiple growth promoting genes and to suppress the ability of oncogenic transcription factors to drive cancer progression. To further elucidate the molecular mechanisms by which ER beta elicits its anti-cancer effects, we developed MDA-MB-231 cells that inducibly express a mutant form of ER beta incapable of directly binding DNA. We demonstrate that disruption of ER beta's direct interaction with DNA abolishes its ability to regulate the expression of well characterized immediate response genes and renders it unable to suppress TNBC cell proliferation. Loss of DNA binding also diminishes the ability of ER beta to suppress oncogenic NF kappa B signaling even though it still physically associates with NF kappa B and other critical co-factors. These findings enhance our understanding of how ER beta functions in this disease and provide a model system that can be utilized to further investigate the mechanistic processes by which ER beta elicits its anti-cancer effects.

Automated summary

Triple negative breast cancer (TNBC) accounts for a high percentage of breast cancer morbidities and mortalities and requires a better understanding of its biology and novel therapeutic approaches. Estrogen receptor beta (ER beta) is expressed in approximately 20% of primary TNBC tumors and is associated with favorable prognostic features. However, the exact mechanisms by which ER beta inhibits cancer progression are not fully understood. This study demonstrates that the direct interaction between ER beta and DNA is essential for its ability to regulate gene expression and suppress TNBC cell proliferation.