Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges

Butti et al. Molecular Cancer (2018) 17:34 https://doi.org/10.1186/s12943-018-0797-x REVIEW Open Access Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges Ramesh Butti1†, Sumit Das1†, Vinoth Prasanna Gunasekaran1†, Amit Singh Yadav1†, Dhiraj Kumar2 and Gopal C. Kundu1* Abstract Breast cancer is a multifactorial disease and driven by aberrant regulation of cell signaling pathways due to the acquisition of genetic and epigenetic changes. An array of growth factors and their receptors is involved in cancer development and metastasis. Receptor Tyrosine Kinases (RTKs) constitute a class of receptors that play important role in cancer progression. RTKs are cell surface receptors with specialized structural and biological features which respond to environmental cues by initiating appropriate signaling cascades in tumor cells. RTKs are known to regulate various downstream signaling pathways such as MAPK, PI3K/Akt and JAK/STAT. These pathways have a pivotal role in the regulation of cancer stemness, angiogenesis and metastasis. These pathways are also imperative for a reciprocal interaction of tumor and stromal cells. Multi-faceted role of RTKs renders them amenable to therapy in breast cancer. However, structural mutations, gene amplification and alternate pathway activation pose challenges to anti-RTK therapy. Keywords: Brest cancer, Tumor microenvironment, Angiogenesis, Cancer Stem cells, Tumor-stroma interaction, Metastasis, Anti-RTK therapy, Drug resistance, Lapatinib, Trastuzumab, Bevacizumab, Alternate pathway activation Background Breast cancer is a major cause of morbidity and mortality among women population worldwide. The incidence of breast cancer differs considerably worldwide. It is expected to affect 0.2 million and would result in an estimated 41,070 deaths in 2017 in USA [1]. Breast cancer emerges as a consequence of dysregulation of different signaling pathways in mammary epithelial cells. Growth factors and chemokines activate various signaling cascades which cross-talk in tumor microenvironment leading to cancer progression. They bind to different families of receptors. Receptor Tyrosine Kinases (RTKs) comprise one such family. RTKs are single-pass transmembrane proteins, expressed on various cell types including the ones in the tumor * Correspondence: † Equal contributors 1 Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, SP Pune University Campus, Pune 411007, India Full list of author information is available at the end of the article microenvironment. Overexpression of various types of RTKs such as epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), insulin-like growth factor receptors (IGFRs), and fibroblast growth factor receptors (FGFRs) is found in different types of cancer including breast [2–4]. Elevated levels of RTKs are associated with increased breast cancer aggressiveness and decreased overall and disease-free survival [5]. Ligand binding leads to conformational changes in RTKs that result in activation of downstream signaling molecules. The important pathways that are known to be activated by RTKs include mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) and phosphoinositide 3kinase (PI3K)/Akt [6–10]. RTK-regulated pathways play key roles in various facets of cancer progression. RTKactivated signaling also induces cancer stem cell (CSC) phenotype that exhibit resistance to therapeutic regimens [6, 9]. Cancer progression is not only regulated by autonomous signaling networks but also context-dependent © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Butti et al. Molecular Cancer (2018) 17:34 molecular signals received from tumor stroma. Tumor stroma consists of various types of non-cancerous cells such as fibroblasts, endothelial cells, macrophages and other immune cells [11]. RTK signaling-regulated interplay between the tumor and stromal cells contributes to tissue remodeling, stromal cell recruitment and activation. Survival of disseminated cancer cells in metastatic sites requires formation of the pre-metastatic niche by stromal cells. Stromal cells expressing RTKs are known to be recruited to metastatic sites and have been found to form pre-metastatic niche through the RTK-regulated signaling [8]. RTKs also regulate trans-differentiation of cancer cells to endothelial cells to form new blood vessels in a process known as vasculogenic mimicry [12, 13]. Since RTKs play important roles in different aspects of breast cancer progression, targeting RTKs might be useful in cancer treatment. Over the years, several RTK inhibitors have been screened and tested in clinical trials. Some of them such as lapatinib, trastuzumab and bevacizumab have been approved by Food and Drug Administration (FDA), USA for clinical management of breast cancer. Interestingly, RTK inhibitors revert conventional therapy-induced multidrug resistance and improve the disease-free survival in metastatic breast cancer patients [14]. Even though anti-RTK therapy shows clinical benefits in breast cancer patients, Page 2 of 18 unfortunately, cancer cells develop de novo or acquired resistance that limits the success of RTK-targeted therapy [15]. In this review, we deal with EGFR, VEGFR, PDGFR and FGFR signaling in breast cancer progression, maintenance of cancer stem cell phenotype, tumor-stroma interaction and drug resistance. Moreover, this review also discusses the major challenges in targeting RTKs for the successful treatment of breast cancer. Structure and classification of RTKs Fifty eight different RTKs have been characterized in humans and they have been classified into 20 different subfamilies on the basis of structural features. Each RTK subfamily exhibits a prototype structural organization along with class-specific characteristics. A prototype RTK has an extracellular ligand-binding domain and intracellular tyrosine kinase domain separated by a transmembrane domain. The subfamilies of RTKs are (1) EGFR, (2) InsR, (3) PDGFR, (4) VEGFR, (5) FGFR, (6) PTK7/CCK4, (7) Trk, (8) Ror, (9) MuSK, (10) Met, (11) Axl, (12) Tie, (13) EphA/B, (14) Ret, (15) Ryk, (16) DDR1/2, (17) Ros, (18) LMR, (19) ALK and (20) SuRTK106/STYK1. The intracellular domai (...truncated)