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ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer

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

Abstract

ERBB3/HER3 is one of the four members of the epidermal growth factor receptor (ERBB) family. It is activated by binding to ligands Neuregulin-1 and Neuregulin-2. Since ERBB3 lacks intrinsic kinase activity, signal transduction occurs through formation of heterodimers with EGFR, ERBB2, and ERBB4. ERBB3 is a signaling specialist since it has six binding sites for the p85 SH2 adapter subunit of phosphoinositide 3’ kinases. These lipid kinases coordinate regulation of metabolism, cell size, proliferation, survival, and angiogenesis. Not surprisingly, ERBB3 signaling has been linked to cancer etiology and progression. In breast cancer, the partnership of ERBB2 and ERBB3 may be crucial for the aggressive properties of cancers with ERBB2 amplification, and may contribute to pre-existing and acquired resistance to therapy. This partnership creates opportunities for improving efficacy of ERBB-targeted pharmaceuticals, by interfering with coupling of ERBB2 to ERBB3 through dimerization inhibitors, and by use of therapeutic compounds that target AKT-dependent pathways activated through ERBB3. Additional therapeutic opportunities may be identified through better understanding of how ERBBs are regulated and deployed in normal mammary gland processes. Work using mouse models has identified the main processes regulated by each of the four ERBBs, which has practical implications in understanding breast cancer etiology, and eventual development of better prognostic, predictive, and therapeutic tools.

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Abbreviations

EGFR:

epidermal growth factor receptor

RTK:

receptor tyrosine kinase

GPCR:

G protein coupled receptor

ER:

estrogen receptor

NRG:

neuregulin

PI3K:

phosphoinositide (3’) kinase

AR:

amphiregulin

TEB:

terminal end bud

IHC:

immunohistochemistry

FISH:

fluorescent in situ hybridization

Tam:

Tamoxifen

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Correspondence to David F. Stern.

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Supported by: USPHS National Cancer Institute R01CA45708

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Stern, D.F. ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer. J Mammary Gland Biol Neoplasia 13, 215–223 (2008). https://doi.org/10.1007/s10911-008-9083-7

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