Estrogen Receptor Beta-p53 Signaling Axis: A New Therapeutic Target in Triple-Negative Breast Cancer
Abstract
The overarching challenges addressed in the proposed research are: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Revolutionize treatment regimens by replacing them with the ones that are more effective, less toxic, and impact survival. There are two estrogen receptors (ERs) in breast cancer: ER-alpha and ER-beta. Until about two decades ago, ER-alpha was the only estrogen receptor known and was simply known as ER. Based on the presence or absence of ER-alpha, breast cancer has been broadly classified as ER-positive and ER-negative. This classification has been very useful in deciding therapy and projecting prognosis as ER-alpha can be targeted by the widely used breast cancer drug tamoxifen (Tam). Although the second receptor, ER-beta, was discovered about 20 years ago, it is still not considered for classification of breast cancers to ER-positive and ER-negative categories. In other words, although a tumor can be considered ER-negative by the conventional criteria, it could still be ER-positive with respect to ER-beta. In fact, several ER-negative (by conventional classification) cancers, including triple-negative (ER-, PR-, and HER2-) breast cancers (TNBC), do have ER-beta. Although the importance of ER-alpha in breast cancer is well documented, the role of ER-beta remains unclear and controversial. ER-beta has been reported to have both pro- and anti-tumor functions. Another important player in breast cancer is the major tumor suppressor called p53. It is functionally inactivated frequently (about 80%) in TNBC by various mechanisms including genetic mutations. Furthermore, mutated p53 (mut-p53), in addition to losing its tumor suppressor capabilities, gains tumor-promoting or "oncogenic" functions. Such mutants are called "gain-of-function p53 mutants." Importantly, ER-beta is expressed in the majority of TNBC. The current proposal is to address the paradoxical dual functionality of ER-beta in light of our preliminary findings and supporting information from scientific publications. Based on our preliminary experimental data, we propose to analyze how the p53 status (normal versus mutant) determines pro- versus anti-tumor functions of ER-beta. We aim to investigate this phenomenon in TNBC cells grown in the laboratory and tumors grown in mice (xenografts). We will validate these findings by directly implanting patient tumor tissues into mice (technically called "Patient-Derived Xenograft" or PDX). The PDXs are more representative of the tumors in the human breast in several characteristics including positive or negative (therapeutic resistance) to various drugs. Furthermore, we propose to complement these studies with investigation of the presence of ER-beta and mut-p53 in an array of TNBC cancer tissues called tissue microarrays (TMAs). The TMAs were generated with tumor tissues from patients who had undergone therapy at the Roswell Park Comprehensive Cancer Center. As detailed information on these patients is archived in electronic format at the Cancer Center in a HIPAA-compliant manner, we will be able to correlate our experimental findings from TMA to various aspects of the disease and treatment including tumor response to therapeutic agents. Tam is a drug widely used for ER-alpha-positive luminal breast cancer. However, when patients with ER-beta-containing breast tumors were treated with Tam, the response had been equivocal and the reason why some such patients responded while others has remained unclear. Research in our laboratory has begun to untangle this important problem. Data from our laboratory show that the p53 status of the TNBC tumor could determine if Tam can be an effective therapeutic agent against these tumors. Importantly, when combined with doxorubicin (Dox)/Adriamycin, Tam lowers several-fold the dose of Dox required for killing TNBC cells. Developing a brand new drug is very costly in terms of time, money, and effort. Translation o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910112
Entities
People
- Benny A Kaipparettu
Organizations
- Baylor College of Medicine
- United States Army