垂体肿瘤，包括催乳素瘤，提出了重大的临床挑战，需要更深入地了解其分子根源，以改进诊断和治疗。在这里，我们使用小鼠模型研究磷酸酶和张力蛋白同源物 (PTEN)/磷酸肌醇 3-激酶 (PI3K) 通路在垂体肿瘤发生中的作用。所有垂体细胞谱系中 Pten 的条件性敲除仅导致雌性小鼠中泌乳素瘤的形成，这证明了 PTEN 在垂体稳态中的关键作用。虽然 Pten 失活会诱导所有垂体细胞中的 Akt 激活，但只有催乳素产生细胞表现出致瘤变化，表明特定的细胞类型效应。催乳素瘤的组织学和分子分析揭示了与人类垂体肿瘤的相似之处，例如血管化和细胞粘附蛋白减少以及细胞周期蛋白积累增加。值得注意的是，泌乳素瘤表现出磷酸化细胞外信号调节激酶（ERK）水平降低，这表明 ERK 在肿瘤发生中的下调。最后，我们分析了一组人类垂体肿瘤中的 PTEN/PI3K 激活。总体而言，我们的研究描绘了 PTEN 和 ERK 信号通路之间复杂的相互作用，为垂体肿瘤发生的性别特异性机制和催乳素瘤的潜在治疗策略提供了见解。版权所有 © 2024。由 Elsevier B.V. 出版。

Pituitary tumors, including prolactinomas, present significant clinical challenges that require a deeper understanding of their molecular roots for improved diagnostics and therapies. Here, we investigate the role of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) pathway in pituitary tumorigenesis using a mouse model. Conditional knockout of Pten in all pituitary cell lineages resulted in prolactinoma formation exclusively in female mice, demonstrating the critical role of PTEN in pituitary homeostasis. While Pten inactivation induced Akt activation in all pituitary cells, only prolactin-producing cells exhibited tumorigenic changes, suggesting specific cell-type effects. Histological and molecular analyses of prolactinomas revealed similarities with human pituitary tumors, such as decreased vascularization and cell adhesion proteins and increased accumulation of cell cycle proteins. Notably, prolactinomas displayed diminished levels of phosphorylated extracellular signal-regulated kinase (ERK), implicating downregulation of ERK in tumorigenesis. Finally, we analyzed PTEN/PI3K activation in a collection of human pituitary tumors. Overall, our study delineates the intricate interplay between the PTEN and ERK signaling pathways, providing insights into sex-specific mechanisms of pituitary tumorigenesis and potential therapeutic strategies for prolactinomas.Copyright © 2024. Published by Elsevier B.V.