Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines

Marzagalli, Monica; Casati, Lavinia; Moretti, Roberta M.; Marelli, Marina Montagnani; Limonta, Patrizia

doi:10.1371/journal.pone.0134396

Cited by 39 publications

(50 citation statements)

References 81 publications

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“…In line with these clinical observations, we recently demonstrated that ERβ, but not ERα, is the ER expressed in human melanoma cell lines, harboring different genetic mutations (A375, BLM, WM115, and WM1552) (110). Moreover, the pattern of expression of the different ERβ isoforms was similar in BLM (NRAS-mutant, BRAF-wild type) and WM115 (BRAF V600D-mutant) melanoma cells: ERβ1 and ERβ5 were found to be expressed at similar levels while ERβ2 showed a higher level of expression.…”

Section: Estrogen Receptor β and Melanomasupporting

confidence: 60%

“…The activity of ERβ agonists was accompanied by an altered expression of the proteins involved in the G1/S transition of the cell cycle (decreased levels of cyclin D1 and cyclin D3, and increased expression of p27, a CDK inhibitor); the apoptosis pathway was not involved in this activity (no change in the cleaved, active form of caspase-3). Importantly, we reported an aberrant global DNA hypomethylation in BLM cells, indicative of genome instability; ERβ activation reverted this hypomethylation status (110). Taken together, these data demonstrate that, in NRAS-mutant melanoma cells, ERβ is associated with an antitumor activity, by causing cell cycle arrest and through the regulation of cell cycle-associated proteins; similar observations were previously reported in different types of cancers expressing this receptor (94, 101, 134–140).…”

Section: Antitumor Activity Of Erβ In Melanomamentioning

confidence: 90%

“…Moreover, the pattern of expression of the different ERβ isoforms was similar in BLM (NRAS-mutant, BRAF-wild type) and WM115 (BRAF V600D-mutant) melanoma cells: ERβ1 and ERβ5 were found to be expressed at similar levels while ERβ2 showed a higher level of expression. On the other hand, in A375 (BRAF V600E-mutant) cells, both ERβ2 and ERβ5 were expressed at higher levels than ERβ1 (110). …”

Section: Estrogen Receptor β and Melanomamentioning

confidence: 96%

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Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to ERβ have been identified. These phytoestrogens decrease the proliferation of melanoma cells. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms. A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology.

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Section: Estrogen Receptor β and Melanomasupporting

confidence: 60%

Section: Antitumor Activity Of Erβ In Melanomamentioning

confidence: 90%

Section: Estrogen Receptor β and Melanomamentioning

confidence: 96%

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Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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“…Melanoma lacks significant oestrogen receptor alpha (ERα) expression, the receptor responsible for the proliferative effects of oestrogen on breast cancer. However, prior reports have demonstrated high oestrogen-receptor beta (ERβ), which may have anti-proliferative activity, 28 in primary melanoma, 29 as well as non-classical oestrogen signaling through a G-protein coupled oestrogen receptor (GPER). 30 Recent studies suggest that GPER signaling in melanocytes may regulate their differentiation status, 30 which has been implicated in resistance to both targeted and immune therapy in this disease.…”

Section: Discussionmentioning

confidence: 99%

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis

McQuade

Daniel

Hess

et al. 2018

The Lancet Oncology

549

459

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Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM

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“…Real-time PCR was performed as previously described57. Briefly, real-time DNA amplification was performed in CFX96 Bio-Rad using 20 μl of total volume.…”

Section: Methodsmentioning

confidence: 99%

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Marelli

Marzagalli

Moretti

et al. 2016

Sci Rep

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Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

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Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines

Cited by 39 publications

References 81 publications

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

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