Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers

Clare G Fedele, Lisa M Ooms, Miriel Ho, Jessica L Vieusseux, Sandra A O'Toole, Ewan K Millar, Elena Lopez-Knowles, Absorn Sriratana, Rajendra Gurung, Laura Baglietto, Graham Giles, Charles G Bailey, John EJ Rasko, Benjamin J Shields, John T Price, Philip W Majerus, Robert L Sutherland, Tony Tiganis, Catriona Ann McLean, Christina Anne Mitchell

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Abstract

Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers; however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.
Original languageEnglish
Pages (from-to)22231 - 22236
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number51
DOIs
Publication statusPublished - 2010

Cite this

Fedele, Clare G ; Ooms, Lisa M ; Ho, Miriel ; Vieusseux, Jessica L ; O'Toole, Sandra A ; Millar, Ewan K ; Lopez-Knowles, Elena ; Sriratana, Absorn ; Gurung, Rajendra ; Baglietto, Laura ; Giles, Graham ; Bailey, Charles G ; Rasko, John EJ ; Shields, Benjamin J ; Price, John T ; Majerus, Philip W ; Sutherland, Robert L ; Tiganis, Tony ; McLean, Catriona Ann ; Mitchell, Christina Anne. / Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. In: Proceedings of the National Academy of Sciences. 2010 ; Vol. 107, No. 51. pp. 22231 - 22236.
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title = "Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers",
abstract = "Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers; however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.",
author = "Fedele, {Clare G} and Ooms, {Lisa M} and Miriel Ho and Vieusseux, {Jessica L} and O'Toole, {Sandra A} and Millar, {Ewan K} and Elena Lopez-Knowles and Absorn Sriratana and Rajendra Gurung and Laura Baglietto and Graham Giles and Bailey, {Charles G} and Rasko, {John EJ} and Shields, {Benjamin J} and Price, {John T} and Majerus, {Philip W} and Sutherland, {Robert L} and Tony Tiganis and McLean, {Catriona Ann} and Mitchell, {Christina Anne}",
year = "2010",
doi = "10.1073/pnas.1015245107",
language = "English",
volume = "107",
pages = "22231 -- 22236",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
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Fedele, CG, Ooms, LM, Ho, M, Vieusseux, JL, O'Toole, SA, Millar, EK, Lopez-Knowles, E, Sriratana, A, Gurung, R, Baglietto, L, Giles, G, Bailey, CG, Rasko, JEJ, Shields, BJ, Price, JT, Majerus, PW, Sutherland, RL, Tiganis, T, McLean, CA & Mitchell, CA 2010, 'Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers', Proceedings of the National Academy of Sciences, vol. 107, no. 51, pp. 22231 - 22236. https://doi.org/10.1073/pnas.1015245107

Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. / Fedele, Clare G; Ooms, Lisa M; Ho, Miriel; Vieusseux, Jessica L; O'Toole, Sandra A; Millar, Ewan K; Lopez-Knowles, Elena; Sriratana, Absorn; Gurung, Rajendra; Baglietto, Laura; Giles, Graham; Bailey, Charles G; Rasko, John EJ; Shields, Benjamin J; Price, John T; Majerus, Philip W; Sutherland, Robert L; Tiganis, Tony; McLean, Catriona Ann; Mitchell, Christina Anne.

In: Proceedings of the National Academy of Sciences, Vol. 107, No. 51, 2010, p. 22231 - 22236.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers

AU - Fedele, Clare G

AU - Ooms, Lisa M

AU - Ho, Miriel

AU - Vieusseux, Jessica L

AU - O'Toole, Sandra A

AU - Millar, Ewan K

AU - Lopez-Knowles, Elena

AU - Sriratana, Absorn

AU - Gurung, Rajendra

AU - Baglietto, Laura

AU - Giles, Graham

AU - Bailey, Charles G

AU - Rasko, John EJ

AU - Shields, Benjamin J

AU - Price, John T

AU - Majerus, Philip W

AU - Sutherland, Robert L

AU - Tiganis, Tony

AU - McLean, Catriona Ann

AU - Mitchell, Christina Anne

PY - 2010

Y1 - 2010

N2 - Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers; however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.

AB - Inositol polyphosphate 4-phosphatase-II (INPP4B) is a regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway and is implicated as a tumor suppressor in epithelial carcinomas. INPP4B loss of heterozygosity (LOH) is detected in some human breast cancers; however, the expression of INPP4B protein in breast cancer subtypes and the normal breast is unknown. We report here that INPP4B is expressed in nonproliferative estrogen receptor (ER)-positive cells in the normal breast, and in ER-positive, but not negative, breast cancer cell lines. INPP4B knockdown in ER-positive breast cancer cells increased Akt activation, cell proliferation, and xenograft tumor growth. Conversely, reconstitution of INPP4B expression in ER-negative, INPP4B-null human breast cancer cells reduced Akt activation and anchorage-independent growth. INPP4B protein expression was frequently lost in primary human breast carcinomas, associated with high clinical grade and tumor size and loss of hormone receptors and was lost most commonly in aggressive basal-like breast carcinomas. INPP4B protein loss was also frequently observed in phosphatase and tensin homolog (PTEN)-null tumors. These studies provide evidence that INPP4B functions as a tumor suppressor by negatively regulating normal and malignant mammary epithelial cell proliferation through regulation of the PI3K/Akt signaling pathway, and that loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas.

UR - http://www.pnas.org/content/107/51/22231.full.pdf+html

U2 - 10.1073/pnas.1015245107

DO - 10.1073/pnas.1015245107

M3 - Article

VL - 107

SP - 22231

EP - 22236

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 51

ER -