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Integrin ?4 regulates SPARC protein to promote invasion.

ABSTRACT: The ?6?4 integrin (referred to as "?4" integrin) is a receptor for laminins that promotes carcinoma invasion through its ability to regulate key signaling pathways and cytoskeletal dynamics. An analysis of published Affymetrix GeneChip data to detect downstream effectors involved in ?4-mediated invasion of breast carcinoma cells identified SPARC, or secreted protein acidic and rich in cysteine. This glycoprotein has been shown to play an important role in matrix remodeling and invasion. Our analysis revealed that manipulation of ?4 integrin expression and signaling impacted SPARC expression and that SPARC facilitates ?4-mediated invasion. Expression of ?4 in ?4-deficient cells reduced the expression of a specific microRNA (miR-29a) that targets SPARC and impedes invasion. In cells that express endogenous ?4, miR-29a expression is low and ?4 ligation facilitates the translation of SPARC through a TOR-dependent mechanism. The results obtained in this study demonstrate that ?4 can regulate SPARC expression and that SPARC is an effector of ?4-mediated invasion. They also highlight a potential role for specific miRNAs in executing the functions of integrins.

SUBMITTER: Gerson KD

PROVIDER: S-EPMC3323016 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Integrin β4 regulates SPARC protein to promote invasion.

Gerson Kristin D KD Shearstone Jeffrey R JR Maddula V S R Krishna VSRK Seligmann Bruce E BE Mercurio Arthur M AM

The Journal of biological chemistry 20120203 13

The α6β4 integrin (referred to as "β4" integrin) is a receptor for laminins that promotes carcinoma invasion through its ability to regulate key signaling pathways and cytoskeletal dynamics. An analysis of published Affymetrix GeneChip data to detect downstream effectors involved in β4-mediated invasion of breast carcinoma cells identified SPARC, or secreted protein acidic and rich in cysteine. This glycoprotein has been shown to play an important role in matrix remodeling and invasion. Our anal ...[more]

PMID: 22308039

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Project description:Molecular apocrine is a subtype of estrogen receptor (ER)-negative breast cancer that is characterized by a steroid-response gene signature. We have recently identified a positive feedback loop between androgen receptor (AR) and extracellular signal-regulated kinase (ERK) signaling in this subtype. In this study, we investigated the transcriptional regulation of molecular apocrine genes by the AR-ERK feedback loop.The transcriptional effects of AR and ERK inhibition on molecular apocrine genes were assessed in cell lines. The most regulated gene in this process, prolactin-induced protein (PIP), was further studied using immunohistochemistry of breast tumors and xenograft models. The transcriptional regulation of PIP was assessed by luciferase reporter assay and chromatin immunoprecipitation. The functional significance of PIP in cell invasion and viability was assessed using siRNA knockdown experiments and the mechanism of PIP effect on integrin-?1 signaling was studied using immunoblotting and immunoprecipitation.We found that PIP is the most regulated molecular apocrine gene by the AR-ERK feedback loop and is overexpressed in ER-/AR+ breast tumors. In addition, PIP expression is regulated by AR-ERK signaling in xenograft models. These observations are explained by the fact that PIP is a target gene of the ERK-CREB1 pathway and is also induced by AR activation. Furthermore, we demonstrated that PIP has a significant functional role in maintaining cell invasion and viability of molecular apocrine cells because of a positive regulatory effect on the Integrin-ERK and Integrin-Akt signaling pathways. In fact, PIP-knockdown markedly decreases the phosphorylation of ERK, Akt, and CREB1. Importantly, PIP knockdown leads to a marked reduction of integrin-?1 binding to ILK1 and ErbB2 that can be reversed by the addition of fibronectin fragments.We have identified a novel feedback loop between PIP and CREB1 mediated through the Integrin signaling pathway. In this process, PIP cleaves fibronectin to release fragments that activate integrin signaling, which in turn increases PIP expression through the ERK-CREB1 pathway. In addition, we demonstrated that PIP expression has a profound effect on cell invasion and the viability of molecular apocrine cells. Therefore, PIP signaling may be a potential therapeutic target in molecular apocrine breast cancer.

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Integrin ?4 regulates SPARC protein to promote invasion.

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Integrin β4 regulates SPARC protein to promote invasion.

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