Amin DN, Campbell MR, Moasser MM.. The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol 21: 944-950

University of California, San Francisco, Medicine, San Francisco, CA 94143-1387, USA.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 12/2010; 21(9):944-50. DOI: 10.1016/j.semcdb.2010.08.007
Source: PubMed


Many types of human cancer are characterized by deregulation of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors. In some cancers, genomic events causing overactivity of individual HER family members are etiologically linked with the pathogenesis of these cancers, and constitute the driving signaling function underlying their tumorigenic behavior. HER3 stands out among this family as the only member lacking catalytic kinase function. Cancers with driving HER3 amplifications or mutations have not been found, and studies of its expression in tumors have been only weakly provocative. However, substantial evidence, predominantly from experimental models, now suggest that its non-catalytic functions are critically important in many cancers driven by its' HER family partners. Furthermore, new insights into the mechanism of activation in the HER family has provided clear evidence of functionality in the HER3 kinase domain. The convergence of structural, mechanistic, and experimental evidence highlighting HER3 functions that may be critical in tumorigenesis have now led to renewed efforts towards identification of cancers or subtypes of cancers wherein HER3 function may be important in tumor progression or drug resistance. It appears now that its failure to earn the traditional definition of an oncogene has allowed the tumor promoting functions of HER3 to elude the effects of cancer therapeutics. But experimental science has now unmasked the unpretentious role of HER3 in cancer biology, and the next generation of cancer therapies will undoubtedly perform much better because of it.

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    • "In fact, among all the erbB dimerization complexes, the erbB2/erbB3 hetero-dimer is the most biologically active and potent for activation of the PI-3 K/Akt signaling cascade [58,59]. Since PI-3 K/Akt signaling is the most important survival pathway in cell proliferation and its activation often leads to multidrug resistance in human cancers [60], it is understandable that one of the major biologic consequences of erbB3 activation is to cause treatment failure in cancer therapy [14]. "
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    ABSTRACT: The erbB receptors, including the epidermal growth factor receptor (EGFR), erbB2 (also known as HER2/neu), erbB3 (or HER3), and erbB4 (or HER4), are often aberrantly activated in a wide variety of human cancers. They are excellent targets for selective anti-cancer therapies because of their transmembrane location and pro-oncogenic activity. While several therapeutic agents against erbB2 and/or EGFR have been used in the treatment of human cancers with efficacy, there has been relatively less emphasis on erbB3 as a molecular target. Elevated expression of erbB3 is frequently observed in various malignancies, where it promotes tumor progression via interactions with other receptor tyrosine kinases (RTKs) due to its lack of or weak intrinsic kinase activity. Studies on the underlying mechanisms implicate erbB3 as a major cause of treatment failure in cancer therapy, mainly through activation of the PI-3 K/Akt, MEK/MAPK, and Jak/Stat signaling pathways as well as Src kinase. It is believed that inhibition of erbB3 signaling may be required to overcome therapeutic resistance and effectively treat cancers. To date, no erbB3-targeted therapy has been approved for cancer treatment. Targeting of erbB3 receptor with a monoclonal antibody (Ab) is the only strategy currently under preclinical study and clinical evaluation. In this review, we focus on the role of erbB3-initiated signaling in the development of cancer drug resistance and discuss the latest advances in identifying therapeutic strategies inactivating erbB3 to overcome the resistance and enhance efficacy of cancer therapeutics.
    Molecular Cancer 05/2014; 13(1):105. DOI:10.1186/1476-4598-13-105 · 4.26 Impact Factor
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    • "Mechanistic studies implicate the function of erbB3 as a major cause of treatment failure in human cancers [23]. In the last several years, our laboratory has focused on studying the biologic features of erbB3 receptor in erbB2+ breast cancer, and published a serious of articles indicating that activation of erbB3 signaling, mainly through PI-3K/Akt pathway, is essential for erbB2-induced therapeutic resistance to tamoxifen [24], paclitaxel [25], and trastuzumab [26]. "
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    ABSTRACT: Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues. The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted.
    Molecular Cancer 11/2013; 12(1):134. DOI:10.1186/1476-4598-12-134 · 4.26 Impact Factor
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    • "Mechanistic studies implicate the function of erbB3 as a major cause of treatment failure in human cancers [20]. Therapeutic targeting of erbB3 is being investigated. "
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    ABSTRACT: Elevated expression of erbB3 rendered erbB2-overexpressing breast cancer cells resistant to paclitaxel via PI-3K/Akt-dependent upregulation of Survivin. It is unclear whether an erbB3-targeted therapy may abrogate erbB2-mediated paclitaxel resistance in breast cancer. Here, we study the antitumor activity of an anti-erbB3 antibody MM-121/SAR256212 in combination with paclitaxel against erbB2-overexpressing breast cancer. Cell growth assays were used to determine cell viability. Cells undergoing apoptosis were quantified by a specific apoptotic ELISA. Western blot analyses were performed to assess the protein expression and activation. Lentiviral vector containing shRNA was used to specifically knockdown Survivin. Tumor xenografts were established by inoculation of BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with paclitaxel and/or MM-121/SAR256212 to determine whether the antibody (Ab) enhances paclitaxel's antitumor activity. Immunohistochemistry was carried out to study the combinatorial effects on tumor cell proliferation and induction of apoptosis in vivo. MM-121 significantly facilitated paclitaxel-mediated anti-proliferative/anti-survival effects on SKBR3 cells transfected with a control vector or erbB3 cDNA. It specifically downregulated Survivin associated with inactivation of erbB2, erbB3, and Akt. MM-121 enhances paclitaxel-induced poly(ADP-ribose) polymerase (PARP) cleavage, activation of caspase-8 and -3, and apoptosis in both paclitaxel-sensitive and -resistant cells. Specific knockdown of Survivin in the trastuzumab-resistant BT474-HR20 cells dramatically enhanced paclitaxel-induced apoptosis, suggesting that increased Survivin caused a cross-resistance to paclitaxel. Furthermore, the studies using a tumor xenograft model-established from BT474-HR20 cells revealed that either MM-121 (10 mg/kg) or low-dose (7.5 mg/kg) paclitaxel had no effect on tumor growth, their combinations significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed that the combinations of MM-121 and paclitaxel significantly reduced the cells with positive staining for Ki-67 and Survivin, and increased the cells with cleaved caspase-3. The combinations of MM-121 and paclitaxel not only inhibit tumor cell proliferation, but also promote erbB2-overexpressing breast cancer cells to undergo apoptosis via downregulation of Survivin in vitro and in vivo, suggesting that inactivation of erbB3 with MM-121 enhances paclitaxel-mediated antitumor activity against erbB2-overexpressing breast cancers. Our data supports further exploration of the combinatorial regimens consisting of MM-121 and paclitaxel in breast cancer patients with erbB2-overexpressing tumors, particularly those resistant to paclitaxel.
    Breast cancer research: BCR 10/2013; 15(5):R101. DOI:10.1186/bcr3563 · 5.49 Impact Factor
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