Oestrogen receptor beta and melanoma: a comparative study

Giorgi, Vincenzo De; Gori, Alessia; Gandini, Sara; Papi, Federica; Grazzini, Marta; Rossari, Susanna; Simoni, Antonella; Maio, Vincenza; Massi, Daniela

doi:10.1111/bjd.12056

Cited by 53 publications

(53 citation statements)

References 38 publications

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“…Moreover, ERβ expression was found to be lower in tumor tissues compared with the adjacent healthy skin. Men showed lower levels of ERβ than women in both melanoma and healthy tissues, in agreement with sex differences in melanoma survival (106). ERβ has been found to be expressed in melanomas of pregnant women more frequently than in men and also a trend to a higher expression in women than in men has been reported.…”

Section: Estrogen Receptor β and Melanomasupporting

confidence: 57%

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: 57%

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

527

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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“…Differences in sun exposure in the population24,28,39–41 might also be in part responsible. An effect of endocrine disruptors is possible42–44 – these could interfere with estrogen receptors and alter the functions of some HOX genes 45–47. It should be noted that the CMM lesions collected in the present study were thin and slow proliferative.…”

Section: Discussionmentioning

confidence: 70%

In vivo skin fluorescence imaging in young Caucasian adults with early malignant melanomas

Pierard¹,

Hermanns‐Lê²,

Pierard³

et al. 2014

CCID

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BackgroundHuman cutaneous malignant melanoma (CMM) is an aggressive cancer showing a dramatic worldwide increase in incidence over the past few decades. The most prominent relative epidemiological increase has been disclosed in young women. The aim of the study was to assess the effects of chronic sun exposures in order to rate the extend of melanocytic stimulations in the vicinity of CMM.MethodsThe study was designed to evaluate the melanin distribution and density using ultraviolet light illumination. The present study was performed on surgical excision specimens of thin CMM lesion removed from the upper limbs of 55 Caucasian adults (37 women and 18 men). Two control groups comprised 23 men and 21 women of similar ages who had medium-size congenital melanocytic nevi, also present on the upper limbs. The peritumoral skin was scrutinized using a Visioscan® VC98 device, revealing the faint mosaic melanoderma (FMM) pattern that grossly indicates early signs of chronic photodamage in epidermal melanin units.ResultsThe median extent of relative FMM was significantly higher in the CMM male group. By contrast, the CMM female group showed a reverse bimodal distribution in FMM size. Only 12/37 (32.5%) of the CMM female group had an increased FMM size, whereas 25/37 (67.5%) of females with CMM had a global FMM extent in the normal range, relative to the controls.ConclusionThin CMM supervening in young women appear unrelated to repeat photoexposure. Other mechanisms are possibly involved.

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Oestrogen receptor beta and melanoma: a comparative study

Abstract: ERβ expression is inversely associated with Breslow thickness and is significantly influenced by sex in MM.

Cited by 53 publications

References 38 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

In vivo skin fluorescence imaging in young Caucasian adults with early malignant melanomas

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