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Nuclear Receptors and Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 46212

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Dr. Zeynep Madak-Erdogan

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Guest Editor

Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
Interests: estrogen receptor; breast cancer; metabolic rewiring; endocrine resistance; metastasis

Dr. Matthew Sikora

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Guest Editor

Department of Pathology, University of Colorado Anschutz Medical Campus; Aurora, CO 80045, USA
Interests: estrogen receptor; breast cancer; steroid hormones; invasive lobular carcinoma; anti-estrogens; wnt signaling

Special Issue Information

Dear Colleagues,

Nuclear receptors (NRs) play important roles in reproductive and nonreproductive tissues and in cancers that originate from these tissues. Cancer patients have benefited tremendously from drugs that target specific nuclear receptor family members, such as androgen receptor for prostate cancer, estrogen receptor for breast cancer, and glucocorticoid receptor to reduce the side effects of therapies. With the advent of recent technological and conceptual advances, we can now expand on these successes to other cancers and nuclear receptors. We invite manuscripts that describe novel actions of nuclear receptors in cancers, including but not limited to how NR-mediated pathways alter tumorigenesis and cancer cell biology, identifying NR-driven cancer cell metabolic dependencies that represent novel cancer therapy targets, diverse roles that the NR family members play in numerous tumor types, how specific co-regulators can drive specific tumor types and specific aspects of cancer cell biology, integrating multi-level omics data to understanding how NR signaling controls tumor biology, dissecting new ways to target NRs, and NR signaling to undermine resistance and NR biology at the population scale.

Dr. Zeynep Madak-Erdogan
Dr. Matthew Sikora
Guest Editors

Manuscript Submission Information

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Keywords

nuclear receptors
cancer
cell biology
metabolism
tumorigenesis
co-regulators
transcription factors
pharmacology
genomics

Published Papers (11 papers)

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Research

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23 pages, 7639 KiB

Open AccessArticle

Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer

by Anne Gallez, Silvia Blacher, Erik Maquoi, Erika Konradowski, Marc Joiret, Irina Primac, Céline Gérard, Mélanie Taziaux, René Houtman, Liesbet Geris, Françoise Lenfant, Elisabetta Marangoni, Nor Eddine Sounni, Jean-Michel Foidart, Agnès Noël and Christel Péqueux

Cancers 2021, 13(10), 2486; https://doi.org/10.3390/cancers13102486 - 20 May 2021

Cited by 18 | Viewed by 4578

Abstract

Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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22 pages, 4533 KiB

Open AccessArticle

Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers

by Eylem Kulkoyluoglu Cotul, Qianying Zuo, Ashlie Santaliz-Casiano, Ozan Berk Imir, Ayca Nazli Mogol, Elif Tunc, Kevin Duong, Jenna Kathryn Lee, Rithva Ramesh, Elijah Odukoya, Mrinali P. Kesavadas, Monika Ziogaite, Brandi Patrice Smith, Chengjian Mao, David J. Shapiro, Ben Ho Park, Benita S. Katzenellenbogen, Drew Daly, Evelyn Aranda, John D. O’Neill, Christopher Walker, Yosef Landesman and Zeynep Madak-Erdogan Show full author list Hide full author list

Cancers 2020, 12(9), 2397; https://doi.org/10.3390/cancers12092397 - 24 Aug 2020

Cited by 10 | Viewed by 4411

Abstract

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER⁺) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER⁺ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER⁺ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD⁺. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER⁺ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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Review

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30 pages, 809 KiB

Open AccessReview

Nuclear Receptor Coregulators in Hormone-Dependent Cancers

by Hedieh Jafari, Shahid Hussain and Moray J. Campbell

Cancers 2022, 14(10), 2402; https://doi.org/10.3390/cancers14102402 - 13 May 2022

Cited by 6 | Viewed by 4457

Abstract

Nuclear receptors (NRs) function collectively as a transcriptional signaling network that mediates gene regulatory actions to either maintain cellular homeostasis in response to hormonal, dietary and other environmental factors, or act as orphan receptors with no known ligand. NR complexes are large and interact with multiple protein partners, collectively termed coregulators. Coregulators are essential for regulating NR activity and can dictate whether a target gene is activated or repressed by a variety of mechanisms including the regulation of chromatin accessibility. Altered expression of coregulators contributes to a variety of hormone-dependent cancers including breast and prostate cancers. Therefore, understanding the mechanisms by which coregulators interact with and modulate the activity of NRs provides opportunities to develop better prognostic and diagnostic approaches, as well as novel therapeutic targets. This review aims to gather and summarize recent studies, techniques and bioinformatics methods used to identify distorted NR coregulator interactions that contribute as cancer drivers in hormone-dependent cancers. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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25 pages, 1103 KiB

Open AccessReview

FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

by Darcie D. Seachrist, Lindsey J. Anstine and Ruth A. Keri

Cancers 2021, 13(20), 5205; https://doi.org/10.3390/cancers13205205 - 17 Oct 2021

Cited by 20 | Viewed by 6675

Abstract

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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19 pages, 584 KiB

Open AccessReview

Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

by Sanjeev Kumar, Allegra Freelander and Elgene Lim

Cancers 2021, 13(19), 4972; https://doi.org/10.3390/cancers13194972 - 3 Oct 2021

Cited by 7 | Viewed by 3232

Abstract

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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25 pages, 1244 KiB

Open AccessReview

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

by Shaimaa Hussein, Pooja Khanna, Neha Yunus and Michael L. Gatza

Cancers 2021, 13(19), 4808; https://doi.org/10.3390/cancers13194808 - 26 Sep 2021

Cited by 5 | Viewed by 2606

Abstract

Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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14 pages, 1680 KiB

Open AccessReview

Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

by Cole D. Davidson, Noelle E. Gillis and Frances E. Carr

Cancers 2021, 13(17), 4254; https://doi.org/10.3390/cancers13174254 - 24 Aug 2021

Cited by 12 | Viewed by 6191

Abstract

There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast, and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway, activation of novel signaling such as JAK1/STAT1, and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA⁺ and triple-negative breast cancers, respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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18 pages, 1090 KiB

Open AccessFeature PaperReview

Somatic Alterations Impact AR Transcriptional Activity and Efficacy of AR-Targeting Therapies in Prostate Cancer

by Gaurav Chauhan and Hannelore V. Heemers

Cancers 2021, 13(16), 3947; https://doi.org/10.3390/cancers13163947 - 5 Aug 2021

Cited by 4 | Viewed by 2628

Abstract

Inhibiting the activity of the ligand-activated transcription factor androgen receptor (AR) is the default first-line treatment for metastatic prostate cancer (CaP). Androgen deprivation therapy (ADT) induces remissions, however, their duration varies widely among patients. The reason for this heterogeneity is not known. A better understanding of its molecular basis may improve treatment plans and patient survival. AR’s transcriptional activity is regulated in a context-dependent manner and relies on an interplay between its associated transcriptional regulators, DNA recognition motifs, and ligands. Alterations in one or more of these factors induce shifts in the AR cistrome and transcriptional output. Significant variability in AR activity is seen in both castration-sensitive (CS) and castration-resistant CaP (CRPC). Several AR transcriptional regulators undergo somatic alterations that impact their function in clinical CaPs. Some alterations occur in a significant fraction of cases, resulting in CaP subtypes, while others affect only a few percent of CaPs. Evidence is emerging that these alterations may impact the response to CaP treatments such as ADT, radiation therapy, and chemotherapy. Here, we review the contribution of recurring somatic alterations on AR cistrome and transcriptional output and the efficacy of CaP treatments and explore strategies to use these insights to improve treatment plans and outcomes for CaP patients. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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33 pages, 2691 KiB

Open AccessReview

Endogenous and Therapeutic Estrogens: Maestro Conductors of the Microenvironment of ER+ Breast Cancers

by Linda A. Schuler and Fern E. Murdoch

Cancers 2021, 13(15), 3725; https://doi.org/10.3390/cancers13153725 - 24 Jul 2021

Cited by 7 | Viewed by 3113

Abstract

Estrogen receptor alpha (ERα) marks heterogeneous breast cancers which display a repertoire of somatic genomic mutations and an immune environment that differs from other breast cancer subtypes. These cancers also exhibit distinct biological behaviors; despite an overall better prognosis than HER2+ or triple negative breast cancers, disseminated dormant cells can lead to disease recurrence decades after the initial diagnosis and treatment. Estrogen is the best studied driver of these cancers, and antagonism or reduction of estrogen activity is the cornerstone of therapeutic approaches. In addition to reducing proliferation of ERα+ cancer cells, these treatments also alter signals to multiple other target cells in the environment, including immune cell subpopulations, cancer-associated fibroblasts, and endothelial cells via several distinct estrogen receptors. In this review, we update progress in our understanding of the stromal cells populating the microenvironments of primary and metastatic ER+ tumors, the effects of estrogen on tumor and stromal cells to modulate immune activity and the extracellular matrix, and net outcomes in experimental and clinical studies. We highlight new approaches that will illuminate the unique biology of these cancers, provide the foundation for developing new treatment and prevention strategies, and reduce mortality of this disease. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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21 pages, 1797 KiB

Open AccessReview

Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

by Lauren K. Jillson, Gabriel A. Yette, Teemu D. Laajala, Wayne D. Tilley, James C. Costello and Scott D. Cramer

Cancers 2021, 13(13), 3272; https://doi.org/10.3390/cancers13133272 - 30 Jun 2021

Cited by 14 | Viewed by 3138

Abstract

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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26 pages, 6272 KiB

Open AccessReview

Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer

by Jianling Xie, Eric P. Kusnadi, Luc Furic and Luke A. Selth

Cancers 2021, 13(13), 3254; https://doi.org/10.3390/cancers13133254 - 29 Jun 2021

Cited by 10 | Viewed by 3612

Abstract

Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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