Understanding somatic activating ESR1 mutation's role in the tumorigenesis of prolactinomas
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Abstract
Pituitary adenomas, specifically prolactinomas, are common indolent neoplasms that can lead to complications due to excessive hormone secretion, local mass expansion, and crowding. Despite being typically managed with medical treatment, resistance to conventional therapy may arise, and in rare cases, aggressive prolactinomas may exhibit uncontrolled growth, atypical behavior, and malignant potential. A recent study has identified a somatic activating ESR1 mutations contribute to prolactinoma pathogenesis, allowing the use of antiestrogen therapy. Our study investigates the in vitro effects of the constitutive activating ESR1 mutation Y537S (ESR1 Y537S) on lactotroph proliferation and prolactin (PRL) production. Our data supports the hypothesis that the gain-of-function ESR1 Y537S exacerbates growth-related pathways, leading to lactotroph proliferation and PRL production. The mechanisms underlying the correlation of ESR1 Y537S gain-of-function mutation, PRL secretion, and cell proliferation are yet to be fully understood. The recent human data from our group significantly emphasizes the relationships between estrogen receptor mutations and tumor progression along with the parallel incidence of these mutations in aggressive treatment-resistant breast cancer. Our research provides new insights into the molecular mechanisms underlying prolactinoma tumorigenesis and aggressiveness, highlighting the potential of antiestrogen therapy as a targeted treatment approach.
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2025