Steroid ligands, the forgotten triggers of nuclear receptor action; implications for acquired resistance to endocrine therapy.

Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

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Abstract P5-04-26: Identification of preclinical mechanisms driving acquired resistance to endocrine therapy in estrogen-receptor positive (ER+) breast cancer cells

10.1158/1538-7445.sabcs18-p5-04-26 ◽

2019 ◽

Author(s):

C Ong ◽

A Daemen ◽

K Merrick ◽

T O'Brien ◽

L Friedman ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Endocrine Therapy ◽

Breast Cancer Cells ◽

Acquired Resistance ◽

Estrogen Receptor Positive

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Abstract P6-04-03: In-depth genomic analysis of acquired resistance to multiple sequential lines of endocrine therapy in breast cancer

10.1158/1538-7445.sabcs19-p6-04-03 ◽

2020 ◽

Author(s):

Arran K Turnbull ◽

Youli Xa ◽

Carlos Martinez-Perez ◽

Olga Oikonomidou ◽

James Meehan ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Acquired Resistance ◽

Genomic Analysis

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Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21114068 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4068 ◽

Cited By ~ 2

Author(s):

Annamaria Salvati ◽

Valerio Gigantino ◽

Giovanni Nassa ◽

Valeria Mirici Cappa ◽

Giovanna Maria Ventola ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Target Genes ◽

Acquired Resistance ◽

Biological Significance ◽

Response To Therapy ◽

Term Survival ◽

Tumor Spread ◽

Long Term Survival

Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies.

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Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Cells ◽

10.3390/cells9102295 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2295

Author(s):

Bradley A. Creamer ◽

Shelly N. B. Sloan ◽

Jennifer F. Dennis ◽

Robert Rogers ◽

Sidney Spencer ◽

...

Keyword(s):

Breast Cancer ◽

Nuclear Receptor ◽

Breast Tissue ◽

Current Knowledge ◽

Acquired Resistance ◽

Pregnane X Receptor ◽

Chemotherapeutic Agents ◽

Bile Acid Metabolism ◽

Cytochrome P450 Enzymes ◽

Cellular Detoxification

Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism. While PXR clearly has important regulatory roles in the liver and gastrointestinal tract, this nuclear receptor also has biological functions in breast tissue. In this review, we highlight current knowledge of PXR’s role in mammary tumor carcinogenesis. The elevated level of PXR expression in cancerous breast tissue suggests a likely interface between aberrant cell division and xeno-protection in cancer cells. Moreover, PXR itself exerts positive effect on the cell cycle, thereby predisposing tumor cells to unchecked proliferation. Activation of PXR also plays a key role in regulating apoptosis, as well as in acquired resistance to chemotherapeutic agents. The repressive role of PXR in regulating inflammatory mediators along with the existence of genetic polymorphisms within the sequence of the PXR gene may predispose individuals to developing breast cancer. Further investigations into the role that PXR plays in driving tumorigenesis are needed.

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Drug-Regulated Expression of Plasmodium falciparum P-Glycoprotein Homologue 1: a Putative Role for Nuclear Receptors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01392-07 ◽

2008 ◽

Vol 52 (4) ◽

pp. 1438-1445 ◽

Cited By ~ 6

Author(s):

David J. Johnson ◽

Andrew Owen ◽

Nick Plant ◽

Patrick G. Bray ◽

Stephen A. Ward

Keyword(s):

Plasmodium Falciparum ◽

Molecular Mechanism ◽

Nuclear Receptors ◽

Nuclear Receptor ◽

Drug Exposure ◽

Receptor Gene ◽

Acquired Resistance ◽

Proximal Promoter ◽

Whole Genome Analysis ◽

P Glycoprotein

ABSTRACT Acquired resistance to therapeutic agents is a major clinical concern in the prevention/treatment of malaria. The parasite has developed resistance to specific drugs through two mechanisms: mutations in target proteins such as dihydrofolate reductase and the bc1 complex for antifolates and nathoquinones, respectively, and alterations in predicted parasite transporter molecules such as P-glycoprotein homologue 1 (Pgh1) and Plasmodium falciparum CRT (PfCRT). Alterations in the expression of Pgh1 have been associated with modified susceptibility to a range of unrelated drugs. The molecular mechanism(s) that is responsible for this phenotype is unknown. We have shown previously (A. M. Ndifor, R. E. Howells, P. G. Bray, J. L. Ngu, and S. A. Ward, Antimicrob. Agents Chemother. 37:1318-1323, 2003) that the anticonvulsant phenobarbitone (PB) can induce reduced susceptibility to chloroquine (CQ) in P. falciparum, and in the current study, we provide the first evidence for a molecular mechanism underlying this phenomenon. We demonstrate that pretreatment with PB can elicit decreased susceptibility to CQ in both CQ-resistant and CQ-sensitive parasite lines and that this is associated with the increased expression of the drug transporter Pgh1 but not PfCRT. Furthermore, we have investigated the proximal promoter regions from both pfmdr1 and pfcrt and identified a number of putative binding sites for nuclear receptors with sequence similarities to regions known to be activated by PB in mammals. Whole-genome analysis has revealed a putative nuclear receptor gene, providing the first evidence that nuclear receptor-mediated responses to drug exposure may be a mechanism of gene regulation in P. falciparum.

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Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2007.05.008 ◽

2007 ◽

Vol 106 (1-5) ◽

pp. 102-110 ◽

Cited By ~ 55

Author(s):

Wei Yue ◽

Ping Fan ◽

Jiping Wang ◽

Yuebai Li ◽

Richard J. Santen

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Endocrine Therapy ◽

Breast Cancer Cells ◽

Acquired Resistance

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Acquired genomic alterations in circulating tumor DNA from patients receiving abemaciclib alone or in combination with endocrine therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3519 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3519-3519

Author(s):

Matthew P. Goetz ◽

Erika Paige Hamilton ◽

Mario Campone ◽

Sara A. Hurvitz ◽

Javier Cortes ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Acquired Resistance ◽

Unmet Need ◽

Point Mutations ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Mechanisms Of Resistance ◽

Genomic Alterations ◽

Tumor Dna

3519 Background: An understanding of the mechanisms of acquired resistance to CDK4 & 6 inhibitors, either alone or with endocrine therapy (ET), is an unmet need. Abemaciclib is a CDK4 & 6 inhibitor approved for treatment of HR+, HER2- advanced breast cancer (ABC). Here we evaluated acquired genomic alterations detected in circulating tumor DNA (ctDNA) from patients (pts) treated with abemaciclib + nonsteroidal aromatase inhibitor (AI) or placebo + AI in MONARCH 3 or abemaciclib monotherapy in nextMONARCH 1. Methods: MONARCH 3 randomized postmenopausal women with HR+, HER2- ABC with no prior systemic therapy in the advanced setting to abemaciclib (150 mg Q12H) or placebo + AI. nextMONARCH 1 randomized women with HR+, HER2- metastatic breast cancer who had progressed on or after prior ET and CT to abemaciclib (150 mg Q12H) + tamoxifen, abemaciclib (150 mg Q12H), or abemaciclib (200 mg Q12H) + loperamide. Plasma from pts in the abemaciclib or placebo + AI arms (MONARCH 3) or abemaciclib monotherapy arms (nextMONARCH 1) was analyzed by the Guardant360 assay to identify potential tumor-related genomic alterations including point mutations, indels, amplifications, and fusions acquired at EOT in comparison with baseline. Results: For MONARCH 3, commonly acquired alterations at EOT included ESR1 (17%), TP53 (10%), EGFR (8%), FGFR1 (7%), and PDGFRA (7%) in the abemaciclib + AI arm, and ESR1 (31%), TP53 (10%), and BRCA1 (7%) in the placebo + AI arm. Acquired alterations more frequent for abemaciclib + AI pts included RB1 (6%), MYC (5%), and AR (5%), compared to 0% in the placebo + AI arm (p = 0.008 RB1; p = 0.015 MYC or AR). In contrast, acquired ESR1 alterations were less frequent with abemaciclib + AI vs placebo + AI (17% vs 31%, p = 0.038). In nextMONARCH 1, the most commonly acquired alterations with abemaciclib monotherapy were in TP53 (10%), EGFR (9%), RB1 (9%), MYC (9%), and MET (8%). In addition, acquired alterations in ESR1 (6%) and AR (3%) were also found. PIK3CA alterations were not frequently acquired (abemaciclib + AI 1%, placebo + AI 6%, abemaciclib monotherapy 5%). Conclusions: Acquired genomic alterations potentially associated with emerging mechanisms of resistance to abemaciclib alone or in combination with AI may include RB1, MYC, or AR alterations, while the acquisition of ESR1 alterations was less common in pts treated with abemaciclib + AI compared to placebo + AI. These findings are hypothesis-generating and provide insight into mechanisms of resistance to abemaciclib vs ET. Clinical trial information: NCT02246621, NCT02747004 .

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