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

Samuel J. Rodgers; Lisa M. Ooms; Viola M.J. Oorschot; Ralf B. Schittenhelm; Elizabeth V. Nguyen; Sabryn A. Hamila; Natalie Rynkiewicz; Rajendra Gurung; Matthew J. Eramo; Absorn Sriratana; Clare G. Fedele; Franco Caramia; Sherene Loi; Genevieve Kerr; Helen E. Abud; Georg Ramm; Antonella Papa; Andrew M. Ellisdon; Roger J. Daly; Catriona A. McLean; Christina A. Mitchell

doi:10.1038/s41467-021-23241-6

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

Samuel J. Rodgers, Lisa M. Ooms, Viola M.J. Oorschot, Ralf B. Schittenhelm, Elizabeth V. Nguyen, Sabryn A. Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J. Eramo, Absorn Sriratana, Clare G. Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E. Abud, Georg Ramm, Antonella Papa, Andrew M. Ellisdon, Roger J. Daly, Catriona A. McLeanChristina A. Mitchell

Research output: Contribution to journal › Article › Research › peer-review

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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.

Original language	English
Article number	3140
Number of pages	19
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23241-6
Publication status	Published - 2021

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10.1038/s41467-021-23241-6Licence: CC BY

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Rodgers, S. J., Ooms, L. M., Oorschot, V. M. J., Schittenhelm, R. B., Nguyen, E. V., Hamila, S. A., Rynkiewicz, N., Gurung, R., Eramo, M. J., Sriratana, A., Fedele, C. G., Caramia, F., Loi, S., Kerr, G., Abud, H. E., Ramm, G., Papa, A., Ellisdon, A. M., Daly, R. J., ... Mitchell, C. A. (2021). INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer. Nature Communications, 12(1), Article 3140. https://doi.org/10.1038/s41467-021-23241-6

@article{e6e2211394a94669994b3a465279bc8c,

title = "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.",

author = "Rodgers, {Samuel J.} and Ooms, {Lisa M.} and Oorschot, {Viola M.J.} and Schittenhelm, {Ralf B.} and Nguyen, {Elizabeth V.} and Hamila, {Sabryn A.} and Natalie Rynkiewicz and Rajendra Gurung and Eramo, {Matthew J.} and Absorn Sriratana and Fedele, {Clare G.} and Franco Caramia and Sherene Loi and Genevieve Kerr and Abud, {Helen E.} and Georg Ramm and Antonella Papa and Ellisdon, {Andrew M.} and Daly, {Roger J.} and McLean, {Catriona A.} and Mitchell, {Christina A.}",

note = "Funding Information: This work was supported by an NHMRC grant APP1104614. This study utilized the Monash Micro Imaging, Monash Histology Platform, Flowcore, Monash Proteomics & Metabolomics Facility, Monash Animal Research Platform, Micromon, Monash Rama-ciotti Centre for Cryo Electron Microscopy, Monash University, Australia. The authors thank Joan Clark (Monash Ramaciotti Centre for Cryo Electron Microscopy) for excellent technical assistance. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

doi = "10.1038/s41467-021-23241-6",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Rodgers, SJ, Ooms, LM, Oorschot, VMJ, Schittenhelm, RB, Nguyen, EV, Hamila, SA, Rynkiewicz, N, Gurung, R, Eramo, MJ, Sriratana, A, Fedele, CG, Caramia, F, Loi, S, Kerr, G, Abud, HE , Ramm, G , Papa, A , Ellisdon, AM , Daly, RJ , McLean, CA & Mitchell, CA 2021, 'INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer', Nature Communications, vol. 12, no. 1, 3140. https://doi.org/10.1038/s41467-021-23241-6

TY - JOUR

T1 - INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

AU - Rodgers, Samuel J.

AU - Ooms, Lisa M.

AU - Oorschot, Viola M.J.

AU - Schittenhelm, Ralf B.

AU - Nguyen, Elizabeth V.

AU - Hamila, Sabryn A.

AU - Rynkiewicz, Natalie

AU - Gurung, Rajendra

AU - Eramo, Matthew J.

AU - Sriratana, Absorn

AU - Fedele, Clare G.

AU - Caramia, Franco

AU - Loi, Sherene

AU - Kerr, Genevieve

AU - Abud, Helen E.

AU - Ramm, Georg

AU - Papa, Antonella

AU - Ellisdon, Andrew M.

AU - Daly, Roger J.

AU - McLean, Catriona A.

AU - Mitchell, Christina A.

N1 - Funding Information: This work was supported by an NHMRC grant APP1104614. This study utilized the Monash Micro Imaging, Monash Histology Platform, Flowcore, Monash Proteomics & Metabolomics Facility, Monash Animal Research Platform, Micromon, Monash Rama-ciotti Centre for Cryo Electron Microscopy, Monash University, Australia. The authors thank Joan Clark (Monash Ramaciotti Centre for Cryo Electron Microscopy) for excellent technical assistance. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-021-23241-6

DO - 10.1038/s41467-021-23241-6

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

UN SDGs

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Other files and links

Characterisation of a novel oncogene in breast cancer

ARC Centre of Excellence in Advanced Molecular Imaging

Molecular markers of phenotype, therapeutic responsiveness and prognosis in human cancers - Improving characterisation of human cancers in order to optimise clinical management and treatment.

Animal Research Platform (MARP)

FlowCore

Histology Platform

Cite this

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

Abstract

UN SDGs

Access to Document

Other files and links

Projects

Characterisation of a novel oncogene in breast cancer

ARC Centre of Excellence in Advanced Molecular Imaging

Molecular markers of phenotype, therapeutic responsiveness and prognosis in human cancers - Improving characterisation of human cancers in order to optimise clinical management and treatment.

Equipment

Animal Research Platform (MARP)

FlowCore

Histology Platform

Cite this