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Wnt5a as an Effector of TGFβ in Mammary Development and Cancer

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

Abstract

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.

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Abbreviations

Ddr1:

Discoidin Domain Receptor 1

DNIIR:

dominant-negative mutation of Tgfbr2

Dsh:

Dishelleved

GSK-3ß:

Glycogen Synthase Kinase-3ß

HGF:

Hepatocyte Growth Factor

JNK:

c-Jun N-terminal kinase

LEF/TCF:

Lymphoid Enhancer Factor/T-Cell-Specific Transcription Factor

MaSCs:

mammary stem cells

MMP:

Matrix Metalloproteinases

PKC:

Phospho Kinase C

Ror2:

receptor tyrosine kinase-like orphan receptor 2

TEBs:

terminal end buds

TGF-ß:

Transforming Growth Factor -beta

Tgfbr1:

TGF-ß receptor type I

Tgfbr2:

TGF-ß receptor type II

Wnt5a:

Wingless-related MMTV Integration Site 5A

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Acknowledgments

Breast cancer research in R. Serra’s laboratory was supported by NIH R01 CA126942. S.E. Baxley was supported by the UAB Cancer Prevention and Control Training Program, NCI R25 CA047888 and MSTP training grant T32 GM008361.

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  1. Department of Cell Biology, University of Alabama at Birmingham, 1918 University Blvd., 660 MCLM, Birmingham, AL, 35294–0005, USA

    Rosa Serra, Stephanie L. Easter, Wen Jiang & Sarah E. Baxley

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  1. Rosa Serra
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  2. Stephanie L. Easter
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  3. Wen Jiang
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  4. Sarah E. Baxley
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Correspondence to Rosa Serra.

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Serra, R., Easter, S.L., Jiang, W. et al. Wnt5a as an Effector of TGFβ in Mammary Development and Cancer. J Mammary Gland Biol Neoplasia 16, 157–167 (2011). https://doi.org/10.1007/s10911-011-9205-5

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  • DOI: https://doi.org/10.1007/s10911-011-9205-5

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