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

Igor Bado¹, Eric Pham², Benjamin Soibam³

¹Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA.

|June 2, 2018

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.

Insights

Estrogen receptor beta (ERβ) collaborates with p53 to suppress tumors in ERα-positive breast cancer. This interaction enhances p53

Area of Science:

Oncology
Molecular Biology
Endocrinology

Background:

Estrogen receptor α (ERα)-positive breast cancers often develop resistance to endocrine and chemotherapy treatments.
Mechanisms regulating chemotherapy response in luminal tumors, despite expressing wild-type p53, remain unclear.
Estrogen receptor beta (ERβ) may inhibit breast tumorigenesis, potentially with p53, but synergistic mechanisms are undescribed.

Purpose of the Study:

To investigate the synergistic mechanism between ERβ and p53 in ERα-positive breast cancer cells.
To determine if ERβ relies on p53 for its tumor-suppressive actions.
To explore the impact of ERβ-p53 interaction on chemotherapy and endocrine therapy resistance.

Main Methods:

Investigated ERβ upregulation and ERβ agonist treatment effects on p53 function.
Analyzed molecular interactions between ERβ and p53.
Assessed the impact of ERβ-p53 interaction on p53 transcriptional activity.
Evaluated chemosensitivity and tamoxifen response in endocrine-resistant cells.

Main Results:

Upregulation of ERβ and ERβ agonists potentiate p53's tumor suppressor function, decreasing cancer cell survival.
A molecular interaction between ERβ and p53 was identified, disrupting ERα's inhibition of p53 and increasing p53 transcriptional activity.
This interaction altered the chemosensitivity of endocrine-resistant cells, including their response to tamoxifen therapy.

Conclusions:

ERβ collaborates with p53 to exert tumor-suppressive effects in ERα-positive breast cancer cells.
Ligand-regulated ERβ can be a therapeutic tool to modulate p53 activity and improve treatment outcomes for resistant breast cancers.
Targeting the ERβ-p53 interaction may offer a novel strategy for managing endocrine-resistant breast cancer.

Read full analysis

Keywords:

DNA damage response breast cancer estrogen receptor β p53 therapy response

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