ErbB3 Ablation Impairs PI3K/Akt-Dependent Mammary Tumorigenesis

Abstract

Summary The ErbB receptor family member ErbB3 has been implicated in breast cancer growth but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt along with tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), ErbB3, and Src, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. Here we report that ErbB3 is critical for PI3K/AKT-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth and pulmonary metastasis. Further EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no mouse toxicity. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.

Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice

“…2 ). This latter fi nding is noteworthy, as high expression of HER3 has been shown to predict early escape from HER-targeted therapies, such as the use of the anti-HER2 monoclonal antibody trastuzumab ( 37 ), and is consistent with a recent report showing that genetic ablation of HER3, or its knockdown by EZN-3920, decreased PI3K signaling and tumor growth in the mouse mammary tumor virus, MMTV-PyVmT , model of BC ( 38 ). Regarding the impact of n-3 PUFAs on HER2 and HER3 signaling, our studies were then extended to cultured cell lines exhibiting moderate expression of HER2 (E0771) and overexpressing HER2 (BT-474 and SK-BR-3), in which we investigated whether DHA could modulate cell proliferation and the HER2 signaling pathway.…”

The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival

“…16 More recently, ErbB3 has also been shown to be essential for tumor onset, survival and activation of the AKT pathway in the MMTV/MT mouse model. 32 Importantly, although ErbB3 deletion or ablation of the p85-binding site in MT significantly delayed mammary tumor onset in MMTV/MT transgenic mice, attenuated SH2-driven ShcA signaling only modestly impaired tumor induction but significantly reduced tumor cell outgrowth. It is possible that these more modest effects on mammary tumor onset may result from ) were injected into the fourth mammary fat pad of Ncr nude mice (Taconic) as previously described.…”

Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models

“…Consistent with this, reduced HER3 expression by conditional knockout or LNA-based antisense molecule, designated as EZN-3920, in a polyoma-T model of breast cancer inhibits PI3K activation and tumor formation in this genetically engineered mouse model (21). In addition, siRNA and short hairpin RNA (shRNA)-directed downmodulation of HER3 resulted in tumor growth inhibition in lung adenocarcinoma (22) and decreased disease progression as well as prolonged survival in xenograft mouse models of ovarian cancer (13) or of HER2-overexpressing breast cancer (5).…”

“…administration of EZN-3920 was detected (30). In addition, the compound downmodulated HER3 and inhibited tumor growth in a mouse model of mammary carcinoma driven by the polyomavirus middle T oncogene (21). On the basis of this initial favorable activity, we decided to extend our efficacy studies in additional models in which HER3 plays a key role in tumor development.…”