Strategies to degrade estrogen receptor α in primary and ESR1 mutant-expressing metastatic breast cancer

Busonero, Claudia; Leone, Stefano; Bartoloni, Stefania; Acconcia, Filippo

doi:10.1016/j.mce.2018.10.020

Cited by 31 publications

(69 citation statements)

References 124 publications

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“…Notably, a similar stimulatory effect of 276 Tam on ERE-containing genes was already scored in different cell lines(Arao et al, 2011). As 277 expected(Busonero et al, 2019;Leclercq et al, 2006), the E2-induced degradation of ERα was 278 prevented by Tam(Fig. 4B).…”

supporting

confidence: 66%

Real-time measurement of E2:ERα transcriptional activity in living cells

Cipolletti

Leone

Bartoloni

et al. 2019

Preprint

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Kinetic analyses of diverse physiological processes have the potential to unveil new aspects of the molecular regulation of cell biology at temporal levels. 17β-estradiol (E2) regulates diverse physiological effects by binding to the estrogen receptor α (ERα), which primarily works as a transcription factor. Although many molecular details of the modulation of ERα transcriptional activity have been discovered including the impact of receptor plasma membrane localization and its relative E2-evoked signalling, the knowledge of real-time ERα transcriptional dynamics in living cells is lacking. Here, we report the generation of MCF-7 and HeLa cells stably expressing a modified luciferase under the control of an E2-sensitive promoter, which activity can be continuously monitored in living cells and show that E2 induces a linear increase in ERα transcriptional activity. Ligand-independent (e.g., epidermal growth factor) receptor activation was also detected in a time-dependent manner. Kinetic profiles of ERα transcriptional activity measured in the presence of both receptor antagonists and inhibitors of ERα plasma membrane localization reveals a biphasic dynamic of receptor behaviour underlying novel aspects of receptor-regulated transcriptional effects. Finally, analysis of the rate of the dose-dependent E2 induction of ERα transcriptional activity demonstrates that low doses of E2 induce an effect identical to that determined by high concentrations of E2 as a function of the duration of hormone administration. Overall, we present the characterization of sensitive stable cell lines where to study the kinetic of E2 transcriptional signaling and to identify new aspects of ERα function in different physiological or pathophysiological conditions.

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supporting

confidence: 66%

Real-time measurement of E2:ERα transcriptional activity in living cells

Cipolletti

Leone

Bartoloni

et al. 2019

Preprint

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“…Treatment of metastatic ER positive BCa is challenging with 30 of patients developing resistance to ET [22,23]. Therapy options for these patients can be broadly categorised into one of three groups, based on their targets: (i) those specifically targeting the ER, (ii) those targeting ER signaling pathways, and (iii) those targeting alternative pathways [99]. Treatment can be a monotherapy or a combination of drugs from these different categories, targeting mutated ER, degradation (proteasome inhibitors), or kinase pathways ( Table 2).…”

Section: Treatmentsmentioning

confidence: 99%

Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability

Jeffreys

Powter

Balakrishnar

et al. 2020

Cells

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Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.

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“…In the case of breast cancer, ERa is a driving factor for the initiation and earlier progressive stages of the disease, while may also confer a positive response to endocrine therapy employed in more advanced stages (Busonero et al, 2018). For NSCLC, ERa expressed in earlier stages may boost tumor initiation, growth, and invasion, while as the disease progresses to a later stage, its role can be different.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor α promotes lung cancer cell invasion via increase of and cross‐talk with infiltrated macrophages through the CCL2/CCR2/MMP9 and CXCL12/CXCR4 signaling pathways

Chang

et al. 2020

Molecular Oncology

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Data analysis of clinical samples suggests that higher estrogen receptor a (ERa) expression could be associated with worse overall survival in some patients with non-small-cell lung cancer (NSCLC). Immunofluorescence results further showed that higher ERa expression was linked to larger numbers of infiltrated macrophages in NSCLC tissues. However, the detailed mechanisms underlying this phenomenon remain unclear. Results from in vitro studies with multiple cell lines revealed that, in NSCLC cells, ERa can activate the CCL2/CCR2 axis to promote macrophage infiltration, M2 polarization, and MMP9 production, which can then increase NSCLC cell invasion. Mechanistic studies using chromatin immunoprecipitation and promoter luciferase assays demonstrated that ERa could bind to estrogen response elements (EREs) on the CCL2 promoter to increase CCL2 expression. Furthermore, ERa-increased macrophage infiltration can induce a positive feedback mechanism to increase lung cancer cell ERa expression via the up-regulation of the CXCL12/CXCR4 pathway. Targeting these newly identified pathways, NSCLC ERa-increased macrophage infiltration or the macrophage-to-NSCLC CXCL12/CXCR4/ERa signal, with anti-estrogens or CCR2/CXCR4 antagonists, may help in the development of new alternative therapies to better treat NSCLC.

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Strategies to degrade estrogen receptor α in primary and ESR1 mutant-expressing metastatic breast cancer

Cited by 31 publications

References 124 publications

Real-time measurement of E2:ERα transcriptional activity in living cells

Real-time measurement of E2:ERα transcriptional activity in living cells

Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability

Estrogen receptor α promotes lung cancer cell invasion via increase of and cross‐talk with infiltrated macrophages through the CCL2/CCR2/MMP9 and CXCL12/CXCR4 signaling pathways

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