The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment

Abstract

Amplification and over expression of erbB2/neu proto-oncogene is observed in 20–30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 due to constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2Ex16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16 derived mammary tumors exhibit several unique features that distinguish it from the conventional ErbB2 models expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2 derived tumors that express luminal keratins, ErbB2ΔEx16 derived tumors exhibit high degree of intra-tumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibited distinct signaling and gene expression profiles that correlated with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal.

Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression

“…First, alterations in histone markers, DNA methylation, and noncoding RNA contribute to tumor heterogeneity [149–152]. Second, splice variants drive tumor heterogeneity such as androgen receptor (AR) variants in prostate cancer [153, 154]. Third, interactions of CAFs with tumor cells could lead to co-evolution of tumor cells and their microenvironment [38, 48, 52].…”

The Tyrosine Kinome Dictates Breast Cancer Heterogeneity and Therapeutic Responsiveness

“…Mice expressing ErbB2Δ16 rapidly develop metastatic breast tumors characterized by the expression of basal and luminal keratins, which differs from wild‐type ErbB2 expressing mammary tumors that are uniformly positive for luminal cytokeratins. Gene expression profiling and RPPA analysis reveal that mammary tumors expressing ErbB2Δ16 are molecularly distinct from wild type ErbB2 expressing breast tumors [Turpin et al, ]. One of the most interesting findings from this study was the observation that ErbB2Δ16‐expressing breast cancer cells are resistant to T‐DM1, the Trastuzumab antibody drug conjugate, while cells expressing wild‐type ErbB2 are sensitive.…”

“…These results have recently been confirmed through the analysis of transgenic mice engineered to inducibly overexpress ErbB2Δ16 in the mammary epithelium [Turpin et al, ]. Mice expressing ErbB2Δ16 rapidly develop metastatic breast tumors characterized by the expression of basal and luminal keratins, which differs from wild‐type ErbB2 expressing mammary tumors that are uniformly positive for luminal cytokeratins.…”

Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer

“…Breast cancer is the second most commonly diagnosed cancer among women, and despite the recent improvements in diagnosis and treatment of the disease, it is still one of the leading causes of death worldwide [1]. Twenty to thirty percent of breast cancers are characterized by the amplification/overexpression of ERBB2/HER2 (human epidermal growth factor receptor 2), which is associated with poor prognosis, aggressive disease characteristics and resistance to chemotherapy [2,3]. In the past 20 years, cancer research has led to the development of highly promising therapeutic agents that mostly target cancer driver proteins and thus antagonize tumor growth and increase survival, also in highly heterogeneous breast cancer [4].…”

“…d Tumor growth in JIMT-1 xenografts treated with T-DM1 and volasertib, individually or in combination. Treatments were started at day 10 after tumor inoculation when tumor volumes reached 100-200 mm3 . Mice were treated with 5 mg/kg T-DM1 (once in 2 weeks intravenously), volasertib (twice a week orally) or combination of the two for 30 days.…”