Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors

Varešlija, Damir; McBryan, Jean; Fagan, Ailís; Redmond, Aisling M.; Hao, Yuan; Sims, Andrew H.; Turnbull, Arran; Dixon, J. M.; Gaora, Peadar Ó; Hudson, Lance; Purcell, Siobhan; Hill, Arnold D.; Young, Leonie S.

doi:10.1158/1078-0432.ccr-15-1583

Cited by 27 publications

(19 citation statements)

References 47 publications

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“…High levels of ligand-independent ER activity have been detected in AI-resistant breast cancer cells selected in vitro or in patient tumor samples collected after the treatment 34,35. These studies have suggested that ligand-independent ER activity may be an acquired trait under therapy selection.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also shown that unliganded ERα binds to 4,000–5,000 sites in the genome 35,40,44. Caizzie et al in their study demonstrated that unliganded ERα regulates ~900 genes that largely overlap with the set of estrogen-induced ER-target genes, suggesting that unliganded ERα may maintain the basal expression of estrogen-inducible ER-target genes 40.…”

Section: Discussionmentioning

confidence: 99%

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Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

Keenen

Kim

2016

BCTT

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Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4) in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+) breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose–response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ERα protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

Keenen

Kim

2016

BCTT

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“…A recent effort utilizing deep sequencing of 106 candidate genes in 11 paired ER+ primary and metastatic tumors identified several genes more frequently mutated in relapsing versus non-relapsing cases, and/or that were associated with inferior survival based upon TCGA data; two novel genes, Lysine Methyltransferase 2C (KMT2C) and EPH Receptor A7 (EPHA7), were linked to adverse outcome (28). Varešlija et al recently analyzed paired primary and local or distant metastatic tissues, and showed altered expression of ER target genes, reflecting changes in ER activity with AI treatment (29). …”

Section: On the Horizonmentioning

confidence: 99%

“…Moving forward, A cautionary note is that utilization of archived plasma in EDTA for ctDNA studies needs further validation, as fresh blood samples might be necessary to give the most accurate assessment of disease status. Ultimately, the therapeutic challenge will include targeting mutant ER with the right agent at the right time during the patient’s disease course, as initial increase in ligand-independent signaling can transition to complete loss of ER target gene expression and signaling over time (29). …”

Section: On the Horizonmentioning

confidence: 99%

New Strategies in Metastatic Hormone Receptor–Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies

Jankowitz

Oesterreich

Lee

et al. 2017

Clinical Cancer Research

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While major advances in our understanding of the molecular underpinnings of hormone receptor-positive (HR-positive) breast cancer have led to new therapies that have substantially improved in patient outcomes, endocrine–resistant disease still remains a leading cause of breast cancer mortality. Comprehensive molecular profiling of breast cancers has highlighted tremendous tumor heterogeneity, and analysis of paired primary and metastatic tumors has shown the evolution that can occur during acquired resistance to systemic therapies. Novel techniques for monitoring tumor load under treatment pressure, including “liquid biopsy” techniques, such as circulating free tumor DNA (cfDNA) and circulating tumor cells(CTCs), have shown promise as biomarkers to direct treatment without invasive tumor biopsies. However, more research is needed to deepen our understanding of breast cancer alterations under treatment pressure in order to reveal mechanisms of drug resistance and apply precision medicine in biomarker-driven clinical trials.

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“…Similar work analyzing hormone-receptor positive breast cancers have mainly been restricted to short-term pre/post neoadjuvant therapy analyses [19][20][21][22] . One of the most comprehensive genomic studies of this type was a multi-platform effort that characterized the clonal architecture of tumors after four months of AI therapy 23 .…”

mentioning

confidence: 99%

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

Priedigkeit

Ding

Horne

et al. 2020

Preprint

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word count: 200ABSTRACT Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER) positive breast cancer. In this study, we performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen-deprivation along with each tumor's matched primary.Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence.Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1 and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common-including outlier gains in TP63 (n=5 cases [42%]),FGFR4 (n=3 [25%]) and TERT (n=3 [25%]). Recurrent losses involved ESR1 (n=5 [42%]), RELN (n=5 [42%]), SFRP4 (n=4 [33%]) and FOSB (n=4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers. Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease, highlights longitudinal RNA-profiling and identifies a common endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

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Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors

Cited by 27 publications

References 47 publications

Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

New Strategies in Metastatic Hormone Receptor–Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences

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