Inhibition of lymphoma vascularization and dissemination by estrogen receptor β agonists

Yakimchuk, Konstantin; Hasni, Mohammad Sharif; Guan, Jiyu; Chao, Mark; Sander, Birgitta; Okret, Sam

doi:10.1182/blood-2013-07-517292

Cited by 48 publications

(62 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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). Surprisingly, in our paper, we could also show that ERβ agonists were ineffective in reducing the proliferation of A375 and WM1552 (V600E BRAF-mutant) melanoma cells, expressing the ER isoform.…”

Section: Antitumor Activity Of Erβ In Melanomasupporting

confidence: 89%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Antitumor Activity Of Erβ In Melanomasupporting

confidence: 89%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…A key role for ERβ in the inhibition of tumor growth in different forms of cancers has been hypothesized [10, 12, 25, 26]. In particular, a recent study carried out in breast cancer suggested that ERβ activation could inhibit cancer cell proliferation through a mechanism that bring into play a marked reduction of G2/M phase as well as triggering autophagy [14].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of ERα exerts pro-proliferative effects, whereas ERβ activates an anti-proliferative signaling pathway through the execution of a specific and complex gene expression program [8, 9]. ERβ represents the main ER expressed in lymphoid malignancies while ERα levels are very low or undetectable [6, 10–12]. ERβ activation by selective agonists was found to inhibit non Hodgkin lymphoma (NHL) growth, both in cell-based- and mouse-models, mainly reducing cell proliferation [10, 12].…”

Section: Introductionmentioning

confidence: 99%

“…ERβ represents the main ER expressed in lymphoid malignancies while ERα levels are very low or undetectable [6, 10–12]. ERβ activation by selective agonists was found to inhibit non Hodgkin lymphoma (NHL) growth, both in cell-based- and mouse-models, mainly reducing cell proliferation [10, 12]. Furthermore, ERβ agonists were able to inhibit lymphoma vascularization and dissemination in mice [12] further supporting their potential use as therapeutic tools.…”

Section: Introductionmentioning

confidence: 99%

“…ERβ activation by selective agonists was found to inhibit non Hodgkin lymphoma (NHL) growth, both in cell-based- and mouse-models, mainly reducing cell proliferation [10, 12]. Furthermore, ERβ agonists were able to inhibit lymphoma vascularization and dissemination in mice [12] further supporting their potential use as therapeutic tools. However, the precise molecular mechanisms of ERβ-activated pathways underlying these effects still remain unidentified.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy

et al. 2016

View full text Add to dashboard Cite

Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% of patients relapse or fail to make complete remission. In addition, patients who achieve long-term disease-free survival frequently undergo infertility, secondary malignancies, and cardiac failure, which are related to chemotherapeutic agents and radiation therapies. Hence, new therapeutic strategies able to counteract the HL disease in this important patient population are still a matter of study. Estrogens, in particular 17β-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) β activation. On these bases, we investigated whether the ligation of ERβ by a selective agonist, the 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ERβ activation led to a reduction of in vitro cell proliferation and cell cycle progression by inducing autophagy. In nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells, ERβ activation by DPN was able to reduce lymphoma growth up to 60% and this associated with the induction of tumor cell autophagy. Molecular characterization of ERβ-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ERβ activation, both DRAM2 and protein 1 light chain 3 (LC3), a key actor in the autophagosome formation, strictly interacted each other and localized at mitochondrial level.Altogether these results suggest that targeting ERβ with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.

show abstract

Maternal survival of patients with pregnancy‐associated cancers in Taiwan – A national population‐based study

Hsu

Yen

et al. 2020

Cancer Medicine

View full text Add to dashboard Cite

show abstract

Inhibition of lymphoma vascularization and dissemination by estrogen receptor β agonists

Abstract: Key Points Estrogen receptor β (ERβ) activation inhibits lymphoma growth, vascularization, and dissemination in vivo. ERβ activation may mechanistically explain differences in gender incidence and prognosis and contribute to new therapies of lymphomas.

Cited by 48 publications

References 51 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

Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy

Maternal survival of patients with pregnancy‐associated cancers in Taiwan – A national population‐based study

Contact Info

Product

Resources

About