Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth.
Date
2024-09
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Attention Stats
Abstract
Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if estrogens affect eosinophil biology in tumors and how this influences ICB efficacy has not been determined. Here, we report that estrogens decrease the number of peripheral eosinophils and TATE, and this contributes to increased tumor growth in validated murine models of breast cancer and melanoma. Moreover, estrogen signaling in healthy female mice also suppressed peripheral eosinophil prevalence by decreasing the proliferation and survival of maturing eosinophils. Inhibiting estrogen receptor (ER) signaling decreased tumor growth in an eosinophil-dependent manner. Further, the efficacy of ICBs was increased when administered in combination with anti-estrogens. These findings highlight the importance of ER signaling as a regulator of eosinophil biology and TATE and highlight the potential near-term clinical application of ER modulators to increase ICB efficacy in multiple tumor types.
Type
Department
Description
Provenance
Subjects
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Artham, Sandeep, Patrick K Juras, Aditi Goyal, Prabuddha Chakraborty, Jovita Byemerwa, Siyao Liu, Suzanne E Wardell, Binita Chakraborty, et al. (2024). Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth. Science advances, 10(39). p. eadp2442. 10.1126/sciadv.adp2442 Retrieved from https://hdl.handle.net/10161/33094.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Suzanne E Wardell
Throughout my career in science, my work has focused in aspects of steroid hormone (progesterone, estrogen, or androgen) receptor activity in breast and prostate cancers. These interests include not only mechanistic studies of receptor activity in treatment naive tumors, but also the role of these receptors in the evolution of resistance to current therapies.
Despite the development of improved therapies, breast cancer remains a leading cause of mortality in women. While a majority of breast cancers are estrogen receptor (ER) positive and respond to endocrine therapies such as tamoxifen or aromatase inhibitors, as many as 50% of patients experience relapse and progression. Recent data has confirmed continued reliance of these cancers on ER signaling, validating this receptor as a therapeutic target even in a relapsed/metastatic setting. The focus of a majority of my work in breast cancer has been the mechanistic evaluation of methods to target ER activity in this setting of resistance, either through the development of improved receptor antagonists or through the identification of targets downstream of, or impinging upon, ER activity that can serve as secondary targets in this setting.
Similarly, the androgen receptor (AR) remains a therapeutic target in prostate cancer throughout treatment progression to end stage prostate cancer. Although several AR antagonists have been developed and approved for the treatment of prostate cancer, AR overexpression, as well as mutation and/or truncation, are observed clinically and have been shown mechanistically to render the current AR antagonists ineffective in the advanced prostate cancer setting. As with our work in breast cancer, we have identified pathways downstream of AR that are essential to prostate cancer progression, and our current work is intended to devise treatment regimens that will be effective in lieu of, or together with, AR antagonists.
In my role as a research assistant professor, I have conducted several animal studies evaluating next-to-clinic therapeutics in clinically predictive models of advanced breast and prostate cancer that I have developed throughout the past several years of studies. The entry of some of these therapeutics, or of mechanistically related molecules, into clinical trials in these patient populations validates this approach.
Binita Chakraborty
Susan Faye Dent
Medical Oncologist with a focus on breast cancer
Associate Director of Breast Cancer Clinical Research
Co-Director Duke Cardio-Oncology Program
Jatin Roper
My laboratory is interested in understanding the molecular mechanisms of stem cell function in the normal intestine and in colorectal cancer using innovative three-dimensional organoid and in vivo platforms. We demonstrated that high fat diet-induced obesity activates peroxisome proliferator-activated receptor delta (PPARd) signaling in intestinal stem cells and progenitor cells, which increases stem cell regeneration and tumor initiation in the colon. We also pioneered novel orthotopic transplantation and in situ CRISPR/Cas9 gene editing models of colorectal cancer that recapitulate the adenoma-carcinoma-metastasis sequence. Research in the laboratory is focused on three main areas: 1) Immune regulation of the intestinal epithelium and colorectal cancer; 2) The effects of diet-induced obesity on regeneration in the intestine; and 3) analysis of colorectal cancer heterogeneity with single-cell mRNA sequencing and genetically engineered mouse models. The overall goal of this research is to develop new treatment approaches for intestinal diseases such as inflammatory bowel disease and colorectal cancer. I am also a gastroenterologist at Duke University Hospital and the Durham VA Hospital. My clinical interests include colorectal cancer screening and gastrointestinal cancer genetics.
Ching-yi Chang
The main focus of my research has been to define the roles of nuclear hormone receptors (NHRs) in the pathogenesis of disease, with a focus on hormone-related cancers.
During earlier stages of my research career, definition of the structural and molecular determinants of NHR receptor biology and pharmacology was the main focus. Information obtained from these studies was used to guide the development of receptor modulators for therapeutic interventions and to gain insights into the pharmacology of estrogen and androgen receptor ligands. More recently, my research has shifted to define receptor-mediated signaling pathways relevant to the pathogenesis of breast and prostate cancers. One example of this is the definition of signaling pathways downstream of the orphan nuclear receptor, estrogen-related receptor alpha (ERRα) in breast cancer. Using gene expression signature defined in breast cancer cells we demonstrated that the activity of ERRα tracks with poor prognosis in all breast cancer subtypes. We confirmed a causal role for ERRα in breast cancer growth in both cellular and xenograft models of breast cancer. More recently, we further defined the role(s) of this receptor in tumor metabolism and validated its utility as a therapeutic target in triple negative breast cancer (TNBC). In addition to the cancer cell intrinsic effects of ERRα, this receptor is also expressed in T cells and in macrophages. We are currently evaluating the impact of modulating ERRα activity in these immune cells and how that influences tumor biology.
Donald Patrick McDonnell
Lab Website
The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.