Loss of the tumor suppressor, PTEN, is one of the most common findings in prostate cancer (PCa). This loss leads to overactive Akt signaling, which is correlated with increased metastasis and androgen independence. However, another tumor suppressor, inositol-polyphosphate 4-phosphatase type II (INPP4B), can partially compensate for the loss of PTEN. INPP4B is up-regulated by androgens, and this suggests that androgen-deprivation therapy (ADT) would lead to hyperactivity of AKT. However, in the present study, we found that in PCa, samples from men treated with ADT, ERβ, and INPP4B expression were maintained in some samples. To investigate the role of ERβ1 in regulation of INPPB, we engineered the highly metastatic PCa cell line, PC3, to express ERβ1. In these cells, INPP4B was induced by ERβ ligands, and this induction was accompanied by inhibition of Akt activity and reduction in cell migration. These findings reveal that, in the absence of androgens, ERβ1 induces INPP4B to dampen AKT signaling. Since the endogenous ERβ ligand, 3β-Adiol, is lost upon long-term ADT, to obtain the beneficial effects of ERβ1 on AKT signaling, an ERβ agonist should be added along with ADT.

肿瘤抑制因子 PTEN 的缺失是前列腺癌 (PCa) 中最常见的发现之一。这种损失导致 Akt 信号过度活跃，这与增加的转移和雄激素独立性相关。然而，另一种肿瘤抑制因子，肌醇-多磷酸 4-磷酸酶 II 型 (INPP4B)，可以部分补偿 PTEN 的损失。INPP4B被雄激素上调，这表明雄激素剥夺疗法（ADT）会导致AKT过度活跃。然而，在本研究中，我们发现在 PCa 中，来自接受 ADT、ERβ 和 INPP4B 表达治疗的男性的样本在一些样本中保持不变。为了研究 ERβ1 在 INPPB 调节中的作用，我们设计了高转移性 PCa 细胞系 PC3 来表达 ERβ1。在这些细胞中，INPP4B 由 ERβ 配体诱导，这种诱导伴随着Akt活性的抑制和细胞迁移的减少。这些发现表明，在没有雄激素的情况下，ERβ1 诱导 INPP4B 抑制 AKT 信号传导。由于内源性 ERβ 配体 3β-Adiol 在长期 ADT 后丢失，为了获得 ERβ1 对 AKT 信号传导的有益作用，应在 ADT 的同时添加 ERβ 激动剂。