LINE-1 Activation in Endocrine-Related Cancers: Molecular Mechanisms and Translational Implications.

Abstract

Long interspersed nuclear element (LINE-1) retrotransposons are increasingly recognized as active molecular players in tumorigenesis, particularly through mechanisms involving genomic instability, epigenetic deregulation, and disruption of transcriptional networks. However, their specific role in endocrine-related cancers remains underexplored despite accumulating evidence of widespread LINE-1 derepression in tumors of the thyroid, adrenal, pituitary, and prostate glands. In this review, we provide a focused synthesis of the mechanistic consequences of LINE-1 reactivation in endocrine tumors. We discuss how hypomethylation of LINE-1 loci and overexpression of retrotransposon-encoded proteins [open reading frame 1 (ORF1p) and open reading frame 2 proteins] may contribute to DNA damage, copy-number alterations, and impaired p53 signaling. We also explore emerging evidence that ORF1p may act as a co-regulator of nuclear hormone receptors, thereby linking retroelement biology with hormone-dependent tumor behavior. Beyond these molecular insights, we highlight translational opportunities rooted in LINE-1 biology, including the use of ORF1p as a surrogate biomarker of epigenetic instability, and therapeutic strategies targeting the retrotransposon life cycle. By bridging foundational mechanisms with endocrine-specific tumor phenotypes, this review positions LINE-1 derepression as a unifying framework with both biological and clinical relevance in endocrine-related cancers.