Sex hormone receptor signaling networks drive pancreatic solid-pseudopapillary neoplasm pathogenesis and therapy

Solid-pseudopapillary neoplasm of the pancreas (SPN) represents a rare pancreatic tumor with a low malignant potential, predominantly affecting young women. This suggests a potential involvement of sex hormones in the development of the tumor. Research has demonstrated the expression of progesterone receptor (PR), estrogen receptor β (ERβ), and androgen receptor (AR) in certain SPN tumor cells, with the activation of these receptors potentially contributing to tumor growth and proliferation. Sex hormones and their receptors modulate these multiple signaling pathways, influencing the progression of SPN at various levels. Notably, the CTNNB1 mutation serves as a pivotal driver of SPN, leading to the inhibition of β-catenin degradation and its nuclear translocation, as well as the abnormal activation of the Wnt signaling pathway. Furthermore, the Notch signaling pathway, the Hedgehog signaling pathway, and the epithelial-mesenchymal transition may also play significant roles. With the deepening understanding of the molecular mechanisms of SPN, especially the revelation of the interactions between sex hormone receptors and signaling pathways, potential targets for endocrine and targeted combination therapy have been identified. It is anticipated that precise combinations of endocrine and targeted therapies will improve the survival rate and quality of life for patients with unresectable or malignant SPN, bringing about a new breakthrough in the treatment of SPN.