ERβ alters the chemosensitivity of luminal breast cancer cells by regulating p53 function

Abstract

Estrogen receptor α (ERα)-positive breast cancers tend to develop resistance to both endocrine therapy and chemotherapy. Despite recent progress in defining molecular pathways that confer endocrine resistance, the mechanisms that regulate chemotherapy response in luminal tumors remain largely elusive. Luminal tumors often express wild-type p53 that is a major determinant of the cellular DNA damage response. Similar to p53, the second ER subtype, ERβ, has been reported to inhibit breast tumorigenesis by acting alone or in collaboration with p53. However, a synergistic mechanism of action has not been described. Here, we suggest that ERβ relies on p53 to elicit its tumor repressive actions in ERα-positive breast cancer cells. Upregulation of ERβ and treatment with ERβ agonists potentiates the tumor suppressor function of p53 resulting in decreased survival. This effect requires molecular interaction between the two proteins that disrupts the inhibitory action of ERα on p53 leading to increased transcriptional activity of p53. In addition, we show that the same interaction alters the chemosensitivity of endocrine-resistant cells including their response to tamoxifen therapy. Our results suggest a collaboration of ERβ and p53 tumor suppressor activity in breast cancer cells that indicates the importance of ligand-regulated ERβ as a tool to target p53 activity and improve the clinical management of resistant disease.

Characteristics, behaviour and role of biomarkers in metastatic triple-negative breast cancer

“…Although ERα and ERβ are encoded by two different genes, they share 96% and 58%–60% homology in the DNA-binding domain and the ligand-binding domain of ERα, respectively 16 41. Despite sharing similar structures and mechanisms of action, the two ER subtypes evoke distinct transcriptional responses and therefore influence cancer cellular processes differently, suggesting independent roles in therapy resistance 42…”

“…Nonetheless, some studies have demonstrated ERβ positivity to be correlated with a more aggressive clinical outcome15 and with the proliferation marker, Ki-67 43–45. ERβ has also been identified as a novel activator of wild-type p53-dependent transcription, which leads to poorer survival of luminal breast cancer cells 42 46–50…”

Good Guy or Bad Guy? The Duality of Wild-Type p53 in Hormone-Dependent Breast Cancer Origin, Treatment, and Recurrence

“…Alternatively, in conditional ERβ and p53 KO mice, Bado and colleagues demonstrated that a concomitant loss of ERβ and p53 induced early onset of basal-like mammary tumors [ 176 ]. In two recent independent publications, ERβ was shown to interact with p53, reduce p53–ERα binding affinity, and antagonize transcription regulation by p53–ERα [ 177 , 178 ]. Thus, if there is competitive binding between the ER proteins with p53, it has been suggested that the ratio of ERβ and ERα may affect estrogen responsiveness in breast cancer [ 178 ].…”

“…In two recent independent publications, ERβ was shown to interact with p53, reduce p53–ERα binding affinity, and antagonize transcription regulation by p53–ERα [ 177 , 178 ]. Thus, if there is competitive binding between the ER proteins with p53, it has been suggested that the ratio of ERβ and ERα may affect estrogen responsiveness in breast cancer [ 178 ]. The pro-apoptosis response of ERβ in breast cancer cells also involved epigenetic changes in the methylation of histones affecting gene regulation and, hence, cellular activities of the cells [ 177 ].…”

“…In essence, the role of p53 as a protector or perpetrator in breast cancer may very well be dependent on the ratio of ERα and ERβ in breast cancer. In turn, the crosstalk between ERα, ERβ, and p53 has the potential to affect hormone-dependent breast cancers responsiveness to endocrine and other breast cancer therapies [ 177 , 178 ].…”