Estrogen receptor β ligation inhibits Hodgkin lymphoma growth by inducing autophagy.

Marina Pierdominici, Angela Maselli, Silvia L. Locatelli, Laura Ciarlo, Giuseppa Careddu, Mario Patrizio, Barbara Ascione, Antonella Tinari, Carmelo Carlo Stella, Walter Malorni, paola matarrese, Elena Ortona

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)8522-8535
Number of pages13
Publication statusPublished - 2017


  • estrogen receptor beta
  • Hodgkin's lymphoma


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