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<p>Phosphoinositide 3-kinase (PI3K) signaling is hyperactivated in ~70% of breast cancers via mutations in oncogenes including <i>PIK3CA</i> or inactivation/depletion of phosphoinositide (PI)-phosphatases. Generation of PI(3,4,5)P<sub>3</sub> by PI3K activates many downstream effectors, including AKT, that induce cellular proliferation in breast cancer. In this context PI(3,4,5)P<sub>3</sub> is tightly regulated by PI-phosphatases, including the tumor suppressor PTEN and inositol polyphosphate 5-phosphatases such as PIPP/INPP5J. PTEN and PIPP dephosphorylate PI(3,4,5)P<sub>3</sub> to form different lipid products, thereby individually regulating AKT activation. PI3K/AKT signaling is complex and the functional interplay between these PI-phosphatases in suppressing this pathway in vivo is unknown. Here, we utilize experimental models of breast cancer, both dependent and independent of <i>PIK3CA</i> mutation. <i>Pipp</i> ablation in <i>Pten</i><sup>+/−</sup> mice increases mammary AKT signaling and cell proliferation, associated with increased hyperplasia and ductal thickening, characteristics linked with mammary epithelial cell transformation. In breast cancer cell lines, combined <i>PIPP</i>/<i>PTEN</i> knockdown increases AKT signaling and cell proliferation, independent of mutant <i>PIK3CA</i>, above any single PI-phosphatase knockdown. Notably, combined <i>PIPP/PTEN</i> loss is observed in a subset of human breast cancers, associated with reduced survival. Collectively, these findings support a model whereby loss of <i>PIPP</i> constitutes a co-operative step towards breast cancer progression in the context of <i>PTEN</i> deficiency.</p><p></p>

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Non-redundant roles of the phosphoinositide phosphatases PTEN and PIPP in PI3K/AKT signaling in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Lisa M. Ooms,
  • Daniel T. Ferguson,
  • Samuel J. Rodgers,
  • Karmanpreet K. Sukhija,
  • Emily I. Jones,
  • Mariah P. Csolle,
  • Hon Yan Kelvin Yip,
  • Roger J. Daly,
  • Tony Tiganis,
  • Catriona A. McLean,
  • Antonella Papa,
  • Christina A. Mitchell

摘要

Phosphoinositide 3-kinase (PI3K) signaling is hyperactivated in ~70% of breast cancers via mutations in oncogenes including PIK3CA or inactivation/depletion of phosphoinositide (PI)-phosphatases. Generation of PI(3,4,5)P3 by PI3K activates many downstream effectors, including AKT, that induce cellular proliferation in breast cancer. In this context PI(3,4,5)P3 is tightly regulated by PI-phosphatases, including the tumor suppressor PTEN and inositol polyphosphate 5-phosphatases such as PIPP/INPP5J. PTEN and PIPP dephosphorylate PI(3,4,5)P3 to form different lipid products, thereby individually regulating AKT activation. PI3K/AKT signaling is complex and the functional interplay between these PI-phosphatases in suppressing this pathway in vivo is unknown. Here, we utilize experimental models of breast cancer, both dependent and independent of PIK3CA mutation. Pipp ablation in Pten+/− mice increases mammary AKT signaling and cell proliferation, associated with increased hyperplasia and ductal thickening, characteristics linked with mammary epithelial cell transformation. In breast cancer cell lines, combined PIPP/PTEN knockdown increases AKT signaling and cell proliferation, independent of mutant PIK3CA, above any single PI-phosphatase knockdown. Notably, combined PIPP/PTEN loss is observed in a subset of human breast cancers, associated with reduced survival. Collectively, these findings support a model whereby loss of PIPP constitutes a co-operative step towards breast cancer progression in the context of PTEN deficiency.