PTEN loss-of-function contributes to hyperactivation of the PI3K pathway and to drug resistance in breast cancer. Unchecked PI3K pathway signaling increases activation of the mechanistic target of rapamycin complex 1 (mTORC1), which promotes tumorigenicity. Several studies have suggested that vacuolar (H+)–ATPase (V–ATPase) complex activity is regulated by PI3K signaling. In this study, we showed that loss of PTEN elevated V–ATPase activity. Enhanced V–ATPase activity was mediated by increased expression of the ATPase H+ transporting accessory protein 2 (ATP6AP2), also known as the prorenin receptor (PRR). PRR is cleaved into a secreted extracellular fragment (sPRR) and an intracellular fragment (M8.9) that remains associated with the V–ATPase complex. Reduced PTEN expression increased V–ATPase complex activity in a PRR-dependent manner. Breast cancer cell lines with reduced PTEN expression demonstrated increased PRR expression. Similarly, PRR expression became elevated upon PTEN deletion in a mouse model of breast cancer. Interestingly, concentration of sPRR was elevated in the plasma of patients with breast cancer and correlated with tumor burden in HER2-enriched cancers. Moreover, PRR was essential for proper HER2 receptor expression, localization, and signaling. PRR knockdown attenuated HER2 signaling and resulted in reduced Akt and ERK 1/2 phosphorylation, and in lower mTORC1 activity. Overall, our study demonstrates a mechanism by which PTEN loss in breast cancer can potentiate multiple signaling pathways through upregulation of the V–ATPase complex. Implications: Our study contributed to the understanding of the role of the V–ATPase complex in breast cancer cell tumorigenesis and provided a potential biomarker in breast cancer.

中文翻译：

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PTEN缺失后V-ATP酶活性升高是乳腺癌中增强致癌信号所必需的

PTEN 功能丧失导致 PI3K 通路的过度激活和乳腺癌的耐药性。未经检查的 PI3K 通路信号会增加雷帕霉素复合物 1 (mTORC1) 的机制靶标的激活，从而促进致瘤性。多项研究表明，液泡 (H+)-ATPase (V-ATPase) 复合物活性受 PI3K 信号传导调节。在这项研究中，我们发现 PTEN 的丧失会提高 V-ATPase 的活性。增强的 V-ATPase 活性是由 ATPase H+ 转运辅助蛋白 2 (ATP6AP2)，也称为肾素原受体 (PRR) 的表达增加介导的。PRR 被切割成一个分泌的细胞外片段 (sPRR) 和一个细胞内片段 (M8.9)，该片段仍然与 V-ATPase 复合物结合。PTEN 表达降低以 PRR 依赖性方式增加 V-ATPase 复合物活性。PTEN 表达降低的乳腺癌细胞系证明 PRR 表达增加。同样，在乳腺癌小鼠模型中 PTEN 缺失后 PRR 表达升高。有趣的是，乳腺癌患者血浆中 sPRR 的浓度升高，并且与富含 HER2 的癌症的肿瘤负荷相关。此外，PRR 对 HER2 受体的正确表达、定位和信号传导至关重要。PRR 敲低减弱了 HER2 信号传导并导致 Akt 和 ERK 1/2 磷酸化减少，并降低 mTORC1 活性。总体而言，我们的研究证明了一种机制，通过该机制，乳腺癌中的 PTEN 缺失可以通过 V-ATPase 复合物的上调来增强多种信号通路。含义：