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HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

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Abstract

The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities.

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Abbreviations

4ICD:

HER4 intracellular domain

TACE:

tumor necrosis factor α converting enzyme

RIP:

regulated intramembrane proteolysis

ICD:

intracellular domain

HRG:

heregulin

TF:

transcription factor

MMTV:

mouse mammary tumor virus

WAP:

whey acidic protein

SH2:

src homology 2

STAT5:

signal transducer and transactivator 5

ChIP:

chromatin immunoprecipitation

NLS:

nuclear localization signal

PgR:

progesterone receptor

SDF-1:

stromal cell-derived factor 1

ERα:

estrogen receptor alpha

ERE:

estrogen response element

pS2:

trefoil factor 1 precursor

BH3:

BCL-2 homology 3

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Acknowledgements

I am grateful to the Jones lab members past and present for their hard work, dedication, and intellectual input during the evolution of this work in progress. Support for these studies has been provided by NCI/NIH grants CA95783 and CA96717, US AMRMC grants DAMD170610418, DAMD170310418, and DAMD170310395, and the Tulane Cancer Center. Our work is dedicated to the courageous daughters, sisters, wives, and mothers battling breast cancer.

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  1. Department of Pathology, University of Colorado Health Sciences Center, 12800 East 19th Avenue, Aurora, CO, 80045, USA

    Frank E. Jones

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Jones, F.E. HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer. J Mammary Gland Biol Neoplasia 13, 247–258 (2008). https://doi.org/10.1007/s10911-008-9076-6

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