Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Qiaozhu Zuo; Yongkang Yang; Yajing Lyu; Chen Yang; Chelsey Chen; Shaima Salman; Tina Yi Ting Huang; Elizabeth E. Wicks; Walter Jackson; Emmanuel Datan; Wenxin Qin; Gregg L. Semenza

doi:10.1016/j.celrep.2023.112164

Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Qiaozhu Zuo, Yongkang Yang, Yajing Lyu, Chen Yang, Chelsey Chen, Shaima Salman, Tina Yi Ting Huang, Elizabeth E. Wicks, Walter Jackson, Emmanuel Datan, Wenxin Qin, Gregg L. Semenza

School of Medicine

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

Abstract

Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

Original language	English (US)
Article number	112164
Journal	Cell Reports
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2023.112164
State	Published - Mar 28 2023

Keywords

CP: Cancer
HIF-1
MET
Plexin-B3
cancer stem cells
focal adhesion kinase
hypoxia
invasion
metastasis
migration
tumor microenvironment

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112164

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@article{d80d123cc1c14be78cb43403ae393167,

title = "Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis",

abstract = "Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.",

keywords = "CP: Cancer, HIF-1, MET, Plexin-B3, cancer stem cells, focal adhesion kinase, hypoxia, invasion, metastasis, migration, tumor microenvironment",

author = "Qiaozhu Zuo and Yongkang Yang and Yajing Lyu and Chen Yang and Chelsey Chen and Shaima Salman and Huang, {Tina Yi Ting} and Wicks, {Elizabeth E.} and Walter Jackson and Emmanuel Datan and Wenxin Qin and Semenza, {Gregg L.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = mar,

day = "28",

doi = "10.1016/j.celrep.2023.112164",

language = "English (US)",

volume = "42",

journal = "Cell Reports",

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TY - JOUR

T1 - Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

AU - Zuo, Qiaozhu

AU - Yang, Yongkang

AU - Lyu, Yajing

AU - Yang, Chen

AU - Chen, Chelsey

AU - Salman, Shaima

AU - Huang, Tina Yi Ting

AU - Wicks, Elizabeth E.

AU - Jackson, Walter

AU - Datan, Emmanuel

AU - Qin, Wenxin

AU - Semenza, Gregg L.

PY - 2023/3/28

Y1 - 2023/3/28

N2 - Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

AB - Intratumoral hypoxia is a microenvironmental feature that promotes breast cancer progression and is associated with cancer mortality. Plexin B3 (PLXNB3) is highly expressed in estrogen receptor-negative breast cancer, but the underlying mechanisms and consequences have not been thoroughly investigated. Here, we report that PLXNB3 expression is increased in response to hypoxia and that PLXNB3 is a direct target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 expression is correlated with HIF-1α immunohistochemistry, breast cancer grade and stage, and patient mortality. Mechanistically, PLXNB3 is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) and MET/SRC/STAT3/NANOG signaling as well as hypoxia-induced breast cancer cell migration, invasion, and cancer stem cell specification. PLXNB3 knockdown impairs tumor formation and lung metastasis in orthotopic breast cancer mouse models.

KW - CP: Cancer

KW - HIF-1

KW - MET

KW - Plexin-B3

KW - cancer stem cells

KW - focal adhesion kinase

KW - hypoxia

KW - invasion

KW - metastasis

KW - migration

KW - tumor microenvironment

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JF - Cell Reports

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ER -

Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis

Abstract

Keywords

ASJC Scopus subject areas

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