HER3 is required for the maintenance of neuregulin‐dependent and ‐independent attributes of malignant progression in prostate cancer cells

Abstract

HER3 (ERBB3) is a catalytically inactive pseudokinase of the HER receptor tyrosine kinase family, frequently overexpressed in prostate and other cancers. Aberrant expression and mutations of 2 other members of the family, EGFR and HER2, are key carcinogenic events in several types of tumors, and both are wellvalidated therapeutic targets. In this study, we show that HER3 is required to maintain the motile and invasive phenotypes of prostate (DU-145) and breast (MCF-7) cancer cells in response to the HER3 ligand neuregulin-1 (NRG-1), epidermal growth factor (EGF) and fetal bovine serum. Although MCF-7 breast cancer cells appeared to require HER3 as part of an autocrine response induced by EGF and FBS, the response of DU-145 prostate cancer cells to these stimuli, while requiring HER3, did not appear to involve autocrine stimulation of the receptor. DU-145 cells required the expression of HER3 for efficient clonogenicity in vitro in standard growth medium and for tumorigenicity in immunodeficient mice. These observations suggest that prostate cancer cells derived from tumors that overexpress HER3 are dependent on its expression for the maintenance of major attributes of neoplastic aggressiveness, with or without cognate ligand stimulation. ' UICCKey words: HER3; ERBB3; invasiveness; tumorigenicity; prostate; breast The 3 transmembrane tyrosine kinases and 1 pseudokinase of the HER family, EGFR/ERBB1, HERs2/ERBB2, HER4/ERBB4 and HER3/ERBB3, are key regulators of the growth, survival, differentiation, motility and invasiveness of many cell types.1 Their activities are engaged upon binding of polypeptide ligands, of which more than 13 are known in humans.1 Although all HER ligands are structurally related to EGF, individual ligands preferentially bind to, and activate, specific HERs. Ligand binding induces conformational changes in the receptors, exposing a dimerization surface through which they associate with other HER proteins, forming homodimers or heterodimers.2 These specific associations transduce additional conformational changes to the cytoplasmic domains of the receptors, eventually exposing and activating their tyrosine kinase catalytic domains.2 Of the 4 HER proteins, HER2 lacks the capacity to capture ligands, and is constitutively poised to associate, through its dimerization surface, either with the 2nd HER2 molecule, or with the EGFR or HER3 after they adopt active conformations upon ligand binding.2 The pseudokinase HER3 lacks a tyrosine kinase catalytic center. Binding of NRG-1 by HER3 causes its prompt heterodimerization with HER2 and activation of the kinase activity of the latter, which in turn phosphorylates the HER3 cytoplasmic domain at specific tyrosine residues.3-5 HER3 can also form heterodimeric complexes with ligand-bound EGFR or HER4 1 , resulting in its transactivation. Several of the induced phosphosites on HER3 recruit and activate phosphatidylinositol-3 0 kinase (PI3K), directly coupling this receptor to AKT-dependent pathways that promote cell motility, invasion and survival. 3,4 ...

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

“…These results suggest a relative role for neuregulin-1 in promoting the cell survival, probably because other ligands, like neuregulin-2, may be involved in activating the signaling through HER3 in these cells. In addition, a recent work describe that HER3 may be activated in a neuregulin-1 independent manner in DU145 cells (22).…”

“…However, the marked differences in the specificity and clinical efficiency of the HER inhibitors in different carcinomas as well as the development of resistances have limited the efficacy of these drugs (18,19). In PCa, EGFR, HER2 and HER3 expression levels are increased as the disease progresses from localized to metastasic and to the androgen-independent state and these receptors have long been implicated in the survival of androgen-independent prostate cancer cells (20)(21)(22)(23). Thus, the HER family members have been considered as potential therapeutic targets in prostate cancer.…”

Toward the Prognostic Significance and Therapeutic Potential of HER3 Receptor Tyrosine Kinase in Human Colon Cancer

“…2 and results in a protein of about 180 KDa (10)(11)(12). HER3 overexpression was illustrated in a wide range of cancers including those of breast, ovary, lung, and prostate, as well as melanoma (13)(14)(15)(16). This genetic feature has been correlated with poor prognosis in most of the cases (15)(16)(17)(18).…”

44: ErbB3 Expression Promotes Tumorigenesis in Pancreatic Adenocarcinoma

“…We postulate that pancreatic cancer cellular proliferation is directly affected by the level of ErbB3 expression. While several groups have shown that silencing of ErbB3 expression diminishes basal cell proliferation, 15,16,27 our study is the first attempt to demonstrate increased pancreatic cancer cell growth with the introduction of exogenous ErbB3. ErbB3 is closely associated with PI3K-AKT signaling 8 and the potency of this receptor signaling cascade is only now being realized.…”

“…Traditionally, it was thought that ErbB3 played a moderator role in cellular proliferation acting as a simple scaffolding partner for the other signaling receptors, such as EGFR and ErbB2. 5 In prostate cancer, 27 lung cancer 28 and melanoma, 29 it has been speculated that the EGFR-ErbB3 heterodimer contributes to tumorigenesis, and here, utilizing pancreatic adenocarcinoma, we identified ErbB3 as the critical, rate-limiting component in EGFR-dependent cellular proliferation. We postulate that pancreatic cancer cellular proliferation is directly affected by the level of ErbB3 expression.…”