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Metastasis Suppressors and Their Roles in Breast Carcinoma

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Clinically and experimentally, primary tumor development and metastasis are distinct processes—locally growing tumors can progress without the development of metastases. The discovery of endogenous molecules that exclusively inhibit metastasis suggests that metastasis is an amenable therapeutic target. By definition, metastasis suppressors inhibit metastasis without inhibiting tumorigenicity and are thus distinct from tumor suppressors. As the biology underlying functional mechanisms of metastasis suppressors becomes clearer, it is evident that metastasis suppressors could be harnessed as direct drug targets, prognostic markers, and to understand the fundamental biology of the metastatic process. Metastasis suppressors vary widely in their cellular localization: they are found in every cellular compartment and some are secreted. In general, metastasis suppressors appear to regulate selectively how cells respond to exogenous signals, by affecting signaling cascades which regulate downstream gene expression. This review briefly summarizes current functional and biochemical data on metastasis suppressors implicated in breast cancer. We also present a schematic integrating known mechanisms for these metastasis suppressors highlighting potential targets for therapeutic intervention.

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Abbreviations

AKT:

v-akt murine thymoma viral oncogene homolog 1

AP2:

Activating protein 2

ARID4A:

AT rich interactive domain 4A

CK2:

Casein kinase 2

CRSP3:

Co-factor required for Sp1 activity

CXCR4:

Chemokine (C-X-C motif) receptor 4

EGFR:

Epidermal growth factor receptor

ET1:

Endothelin 1

GM-CSF:

Granulocyte macrophage-colony stimulating factor

GPR54:

G-protein coupled receptor 54

GSK1:

Glycogen synthase kinase 1

GTPase:

Guanine tri-phosphatase

HER2:

Human epidermal growth factor receptor 2

HLA-DR:

Human leucocyte antigen-DR

IL8:

Interleukin 8

JNK:

c-Jun NH2 terminal protein kinase

KSR:

Kinase suppressor of Ras

MAPK:

Mitogen activated protein kinase

MHC1:

Major histocompatibility complex class 1

MLK3:

Mixed lineage kinase 3

MPA:

Medroxyprogesterone acetate

HDAC:

Histone deacetylase

NF-κB:

Nuclear factor-kappa B

NMU:

Neuromedin U

PI3K:

Phosphatidyl inositol 3-kinase

PtdIns(4,5)P2 :

Phosphatidyl inositol (4,5) bisphosphate

PMA:

Phorbol myristate acetate

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

RBBP1:

Retinoblastoma binding protein 1

RhoGAP:

Rho GTPase-activating protein

SDF-1:

Stromal derived factor-1

SUDS3:

Suppressor of defective silencing 3

TGF-β:

Transforming growth factor-β

TXNIP:

Thioredoxin interacting protein

VDUP1:

Vitamin D upregulated protein 1

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor 1

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Acknowledgments

KSV is supported by a post-doctoral fellowship (PDF1122006) from the Susan G. Komen For The Cure. Work from the Welch laboratory has been generously supported by US Public Health Service grants CA62168, CA87728, CA89019, U.S. Army Medical Research and Materiel Command grants DAMD-17-01-0358, DAMD-17-02-1-0541, and DAMD17-03-01-0584 and the National Foundation for Cancer Research—Center for Metastasis Research. We wish to thank members of the Welch lab for their critical review of this manuscript and excellent suggestions.

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  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Kedar S. Vaidya & Danny R. Welch

  2. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  3. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  4. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  5. National Foundation for Cancer Research—Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  6. University of Alabama at Birmingham, G-019 Volker Hall, 1670 University Blvd., Birmingham, AL, 35294, USA

    Danny R. Welch

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Vaidya, K.S., Welch, D.R. Metastasis Suppressors and Their Roles in Breast Carcinoma. J Mammary Gland Biol Neoplasia 12, 175–190 (2007). https://doi.org/10.1007/s10911-007-9049-1

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