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15417786mcr200088-sup-236341_2_supp_6330229_qb9fgz.png (221.47 kB)

Supplemental Figure 3 from Elevated V–ATPase Activity Following PTEN Loss Is Required for Enhanced Oncogenic Signaling in Breast Cancer

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posted on 2023-04-03, 17:25 authored by Amro H. Mohammad, Sung-Hoon Kim, Nicholas Bertos, Wissal El-Assaad, Ipshita Nandi, Harvey Smith, Jieyi Yang, Owen J. Chen, Isabelle Gamache, Trisha Rao, Bruno Gagnon, Tina Gruosso, Michel L. Tremblay, Nahum Sonenberg, Marie-Christine Guiot, William Muller, Morag Park, Jose G. Teodoro

This figure contains clinical data that complement the observations made in Figure 4.

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ARTICLE ABSTRACT

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. 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.

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