INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

Abstract

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

“…To further explore the potential mechanism of INPP4B inhibiting myeloma cells proliferation, we detected the effect of INPP4B on PI3K/Akt signaling pathways according to the previous reports ( 16 ). Since mTORC2 phosphorylates Akt at S473 ( 21 ), and RICTOR, a core component of mTORC2, acts as a key effector molecule of the PI3K-Akt pathway ( 22 ), we detected the key regulators, including Akt, p-Akt (thr308), p-Akt (ser473), and rictor-mTOR complex (mTORC2) in MM cells with INPP4B gain or loss of functions.…”

“…Recently, increasing evidence showed that INPP4B is a negative regulator of the PI3K/Akt signaling pathway in many cancers (14). INPP4B inhibited PI3K/Akt signaling pathway suppresses PI3K/Akt signaling by converting PI (3,4)P(2) to PI(3)P (15,16). Furthermore, loss of INPP4B protein expression in breast and ovarian cancer is associated with decreased patient survival (17).…”

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

“…As a consequence, loss of INPP4B prolongs both PI3K and ERK activation [ 42 ]. In addition, recent findings suggest that INPP4B facilitates PI3KCA crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2-to-PI(3)P conversion on late endosomes, suggesting that these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies [ 43 ].…”

INPP4B drives lysosome biogenesis to restrict leukemic stem cell differentiation and promote leukemogenesis

“…Indeed, numerous studies have confirmed that INPP4B suppresses breast, ovarian, skin, and prostate cancer among others [17][18][19][20][21] . However, studies in AML 11,[22][23][24][25] and other malignancies [26][27][28][29] demonstrate that INPP4B can have oncogene-like roles which promote the progression of cancer. These findings prompted us to investigate specific tumour-promoting roles of INPP4B in leukemogenesis.…”

“…We previously reported that expression of Inositol Polyphosphate-4-Phosphatase Type II (INPP4B), a lipid phosphatase that hydrolyzes phosphatidylinositol-3,4-bisphosphate [PtdIns(3,4)P2] to generate phosphatidylinositol-3-monophosphate [PtdIns(3)P], is elevated in the leukemic blasts of approximately one quarter of all AML patients and is associated with poor prognosis (Dzneladze et al, 2015). The notion that high INPP4B expression can drive tumorigenesis was supported by several studies studies in AML (Dzneladze et al, 2015;Recher, 2015;Rijal et al, 2015;Wang et al, 2016;Zhang et al, 2017) and other malignancies (Chi et al, 2015;Gasser et al, 2014;Guo et al, 2016;Rodgers et al, 2021). These findings prompted us to investigate specific tumour-promoting roles for INPP4B in leukemogenesis.…”