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Somatostatin and Epidermal Growth Factor Receptors: Implications in
Breast Cancer
Geetanjali Kharmate and Ujendra Kumar Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada. Received on May 30, 2013; Accepted on June 8, 2013; Published on June 22, 2013 Correspondence should be addressed to Ujendra Kumar; Phone: (604) 827-3660 , Fax: (604) 822-3035 , Email: [email protected] Abstract
Despite several advances, the underlying mechanism G-protein coupled somatostatin receptors (SSTRs) of complexity of breast cancer progression still re- have been recognized as negative regulators of breast mains elusive. In addition to the genetic predisposition, tumors. The activation of SSTRs modulates down- several growth factor receptors including insulin stream signaling responsible for tumor growth and growth factor receptor (IGF), platelet derived growth consequent cytostatic or cytotoxic effects on tumor factor (PDGF) and vascular endothelial growth factor proliferation. SSTR subtypes are well characterized to (VEGF) relaying proliferative signals are accountable form homo-and/or heterodimers within the same fam- for disease progression. Epidermal growth factor re- ily as well as with other GPCRs. Clinically, the chi- ceptors (EGFRs, or commonly known as ErbBs), meric molecule targeting both SSTR5 and dopamine members of the receptor tyrosine kinase family receptors (specifically dopamine receptor 2) is in use (RTKs), play a central role in tumor growth, progres- for the treatment of pituitary tumors. This review de- sion and metastatic disease. Typically, agonist depend- scribes the interplay between SSTRs and EGFR and ent activation of EGFR results in receptor phosphory- the potential role of such cross talk in attenuation of lation, homo- and/or heterodimerization and modula- EGFR-mediated signaling pathways involved in tu- tion of signaling pathways leading to cell proliferation, morigenesis. Furthermore, recent findings supporting survival and metastasis. Targeting one or multiple the role of SSTR in EGFR-mediated signaling in tu- steps in EGFR-mediated tumor progression may serve mor biology are discussed in detail. as a better approach in drug therapies. Unlike EGFRs, mutations in p53 and loss of PTEN are associated with a high risk of breast cancer (Tsutsui et al. 2005). Cur- Breast cancer is a complex heterogeneous form of can- rent studies are focused on defining and identifying cer affecting 1 in 9 women worldwide. Each year, prognostic biomarkers including BRCA1 and BRCA2 more than a million new cases of breast cancer and genetic mutations, estrogen/progesterone (E/P) status 400,000 deaths are globally reported. While 90-95% and expression of p53/PTEN. The identification of are sporadic only 5-10% of all breast cancer cases are such new biomarkers and their implication in progno- hereditary (Rosen et al. 2003). Breast cancer progres- sis and diagnosis has enhanced the understanding of sion is often manifested by excessive cell proliferation, the etiology of breast tumors and the application of genetic mutations, angiogenesis and metastasis. More individualized targeted therapies against tumor pro- than 20-30% of the total hereditary breast tumors are gression while reducing death rates (Weigel & due to inherited genetic mutations in breast cancer 1- Dowsett 2010). Despite such advances, classical mark- susceptibility genes (BRCA1) and BRCA2 (Easton et ers including E, P and epidermal growth factor recep- al. 1995, Rosen et al. 2003, Wooster et al. 1995). The tors (ErbBs) are routinely assessed for diagnostic and amplification of the cmyc gene is observed in 20-30% pathological examinations in breast cancer. So far, an of breast tumors and linked with aggressive metastatic extensive amount of research has been directed to the tumors of high grade (Deming et al. 2000). In normal factors responsible for tumor progression, including breast tissue, p53 and phosphatase and tensin homolog EGFR; however, the potential significance of certain (PTEN) function as tumor suppressor genes; however, receptor proteins such as somatostatin receptors Journal of Molecular Biochemistry (2013) 2, 106-122
The Author(s) 2013. Published by Lorem Ipsum Press.
107 Journal of Molecular Biochemistry, 2013
(SSTRs), which are responsible for tumor suppression, tory showed a receptor-specific colocalization between has not been studied in detail. More importantly, the SSTRs and ErbBs in human breast cancer cells (Watt physiological significance and pharmacological inter- & Kumar 2006). These observations indicate the possi- action between such receptor proteins remains to be bility of a potential functional interaction between SSTRs and ErbBs in breast cancer. Nevertheless, the The role of ErbB1 (commonly known as mechanistic role of SSTRs in the modulation of EGFR EGFR) in human malignancies including neck, head, homo- and/or heterodimerization, phosphorylation and colon and breast has been investigated extensively and consequent inhibition of downstream signaling path- thus remains the major target for anti-neoplastic drug ways remains elusive. The main emphasis of this re- discovery (Nicholson et al. 2001, Yarden 2001, view is to define the mechanisms that might be associ- Zimmermann et al. 2006). Interestingly, the EGFR and ated with the interaction of SSTR and ErbB subtypes ErbB2 subtypes are over-expressed in > 30% of tu- and their pronounced impact in the modulation of sig- mors with poor survival (Abd El-Rehim et al. 2004, naling pathways which are critical in tumor progres- Bo et al. 2008). Hyperactivity due to autocrine secre- sion and inhibition. tion in the ErbB network leads to over-production of ligands and receptors by the breast tumor cells. EGFR- Epidermal Growth Factor Receptors
mediated breast tumor progression is manifested by (i) Epidermal growth factor (EGF) regulates normal as over-expression, (ii) EGFR phosphorylation and (iii) well as neoplastic cell growth. EGF mediates its bio- homo and/or heterodimerization, preferentially with logical effects via ErbBs. Ullrich et al. (1984) first ErbB2, leading to aberrant downstream signaling path- identified EGFR as the cell surface receptor in malig- ways (Bo et al. 2008, Earp et al. 1995, Kallergi et al. nant cells and characterized it using molecular cloning 2008, Kraus et al. 1987, Martin & Philippe 2008, techniques. The ErbB family is comprised of four Olayioye et al. 2000, Ullrich et al. 1984, Yarden transmembrane receptors (EGFR-4) that belong to the 2001). Numerous therapies including tyrosine kinase receptor tyrosine kinase (RTK) family (Carpenter et al. inhibitors (e.g., Lapatinib, Gefitinib and erlotinib) and 1978, Yarden 2001). ErbBs are commonly comprised monoclonal antibodies ( e.g. trastuzumab, cetuximab) of three components: (i) the ligand-binding extracellu- are clinically available, however, targeting EGFR lar (EC) domain, (ii) the hydrophobic transmembrane alone has been deemed insufficient as a means of con- region and, (iii) the intracellular cytoplasmic domain trolling the progression of breast tumors (Alvarez et al. that is linked with the former and contains the tyrosine kinase domain (Harris et al. 2003, Savage et al. 1972). In retrospect, the anti-proliferative role of The extracellular domain is comprised of four subdo- somatostatin (SST), a multifunctional endogenous mains designated as large domains (L1 and L2) and regulatory neuropeptide has been employed for the cysteine rich domains (C1 and C2) (Bajaj et al. 1987, treatment of tumors of different origins (Ben-Shlomo Garrett et al. 2002, Ogiso et al. 2002). The intracellu- & Melmed 2008, Buscail et al. 1995, 2002). The bio- lar domain of ErbBs consists of a highly conserved logical effects of SST are mediated by five membrane tyrosine kinase and C-terminal domain, involved in bound SSTR1-5 belonging to the G-protein coupled phosphorylation and transmission of downstream sig- receptor family (Patel 1999). SSTRs are also known to naling (Garrett et al. 2002, Ogiso et al. 2002). There is regulate secretion of most, if not all, endocrine/ a 53% structural homology within all the ErbB sub- exocrine hormones and growth factors. SSTRs activate types, not accounting for the differences in the tyrosine various downstream targets and negatively regulate kinase domains (Jorissen et al. 2003). EGFR upon cell proliferation (Bousquet et al. 2004, Florio et al. binding to EGF interacts with other ErbBs to activate 1999, 2000, Hagemeister & Sheridan 2008, Lahlou et the tyrosine kinase residues. However, ErbB2 is the al. 2004). The activation of SSTRs promotes homo- only subtype which does not bind to any ligands and and/or heterodimerization within the same family and depends on other ErbBs, preferentially EGFR and with other GPCRs and results in the modulation of ErbB3, for its activation and functionality. ErbB3 downstream signaling cascades more efficiently com- uniquely lacks inherent receptor kinase activity and pared to the native receptors (Grant et al. 2004, Grant relies on other ligand-activated ErbBs for its function & Kumar 2009, Pfeiffer et al. 2002, Rocheville et al. (Guy et al. 1994). The expression of ErbB4, in general, 2000a, b, Saveanu et al. 2002, Somvanshi et al. 2011). is relatively less than of other ErbB subtypes. ErbB4, SSTRs have been clinically proven effective in sup- although having a tyrosine kinase domain, requires pressing pituitary and pancreatic tumor growth (Ben- cleavage by membrane proteases to activate the intra- Shlomo & Melmed 2008, Bousquet et al. 2004, Jaquet cellular tyrosine and its translocation to the cell surface et al. 2005). A recent study from the authors' labora- (Rio et al. 2000). Journal of Molecular Biochemistry, 2013 108
The ligands for ErbBs are classified into three (Abd El-Rehim et al. 2004, Normanno et al. 2006). major groups depending on the receptor binding speci- Breast tumors expressing EGFR and ErbB2 are associ- ficity. The first class consists of EGF and EGF-like
ated with poor clinical outcome (DiGiovanna et al. binding ligands, tumor growth factor-α (TGF-α) and 2005, Toi et al. 1994). ErbB2 is likely to have a higher amphiregulin (AR) that specifically bind to EGFR oncogenic transforming ability in comparison to (Gullick 2001, Suo et al. 2002, Yarden 2001). The sec- EGFR. Overexpression, gene amplification and recep- ond class is composed of betacellulin (BCT), heparin tor mutations have been demonstrated in different tu- binding-EGF and epiregulin that bind to EGFR and mor types. In addition, co-expression of ErbB subtypes ErbB3. The third is the neuregulins (NRGs) family that enhances the transforming ability of breast cancer is further sub grouped into NRG1 and NRG2 that bind cells. An elegant study by DiGiovanna et al. (2005) to ErbB3 and ErbB4 whereas NRG3 and NRG4 bind reported that 15% of the 807 invasive breast tumors only to ErbB4 (Yarden 2001). Of the four receptors, expressed EGFR and that the majority of these tumors ErbB2 is the only receptor subtype that does not bind (87%) co-expressed ErbB2 establishing a striking cor- to any known ligand and relies on other ligand acti- relation between the expression of these two factors in vated ErbBs for its physiological functions (Suo et al. breast cancer patients. Consistent with these observa- tions, studies have also revealed that tumors with co- Prior to ligand binding, EGFR exists as a dor- expression of EGFR/ErbB2/ErbB3 or ErbB2/ErbB3 mant monomer within the cell membrane. Receptor have a more aggressive phenotype than tumors co- dimerization leads to conformational changes and ex- expressing ErbB3/ErbB4 (Abd El-Rehim et al. 2004). posure of the dimerization loop (Gadella & Jovin The overexpression of EGFR and ErbB2 is 1995). These alterations bring two EGFR molecules in often accompanied by elevated production of ligands close proximity allowing receptor dimerization, pro- such as EGF and transforming growth factor-β (TGF- vided there is a 1:1 ligand receptor complex. Binding β) as well as hyperactivated downstream signaling of the two EGF molecules to EGFR stabilizes this cascades (Normanno et al. 2006, Pilichowska et al. complex formation (Lemmon et al. 1997). Binding of 1987). Immunohistochemical analysis of breast carci- EGF to EGFR not only promotes homodimerization nomas revealed that more than 65% of cases were but also heterodimerization with other ErbBs (Earp et positive for EGF and TGF-a. In aggressive breast can- al. 1995). cer, EGF not only enhances mitogen activated protein kinase (MAPK) phosphorylation but is also associated EGFR and Breast Cancer
with sustained and prolonged basal ERK1/2 expression ErbBs are expressed in tissues of epithelial, mesenchy- (Thottassery et al. 2004). Kallergi et al. (2008) demon- mal and neuronal origin and involved in embryonic strated that circulating tumor cells in blood samples development through adulthood. Preponderance of from breast cancer patients expressed phosphorylated data from transgenic and knockout models has indi- EGFR and ErbB2 in the early stages of the disease as cated the role of EGFR in the development and normal well as in metastatic tumors. Additionally, these cells functioning of tissues, most importantly in the brain also displayed high levels of phosphatidylinositol-3- and mammary gland (Alroy & Yarden 1997, Chryso- kinase (PI3K)/AKT phosphorylation. Any mutations in gelos & Dickson 1994, Gospodarowicz 1981, Herbst PI3K and AKT are associated with loss of PTEN and over-expression of ErbB2 (Kallergi et al. 2007a, b). EGF and its cognate receptors play an impor- Recently, nuclear translocation of EGFR was shown to tant role in the normal development of the mammary exert a potential role in breast tumor cells associated gland. However, an imbalance in the regular cellular with enhanced cell proliferation and with the induction process of growth, repair and programmed cell death of cyclin D1, a positive regulator of cell proliferation of the mammary gland leads to tumor formation. Aber- (Lo et al. 2005, Wang et al. 2010). rant functioning of EGFR is implicated in numerous human diseases including Alzheimer's, cardiac dys- Molecular Signaling of EGFR
function, psoriasis and skin lesions as well as psycho- EGF binding to its cognate receptor induces dimeriza- logical disorders including schizophrenia (Chaudhury tion, phosphorylation and internalization of the EGFR et al. 2003, Hahn et al. 2006, King et al. 1990, Suzuki that triggers a network of intricate signaling. Among et al. 2002). However, the most studied role of EGFR various signaling cascades, four major pathways that is in tumorigenesis. EGFR and ErbB2 are the most are regulated by EGFR include Janus kinase (JAK), studied prototype of ErbBs associated with the pro- signal transducers and activators of transcription gression of breast cancer (Olayioye et al. 2000). A to- (STAT), phospholipase C (PLC) and protein kinase C tal of 40-50% of breast carcinomas express ErbBs (PKC) pathways (Alroy & Yarden 1997, Citri & 109 Journal of Molecular Biochemistry, 2013
Yarden 2006, Darnell et al. 1994, Jorissen et al. 2003, phate (GTP). Activated Ras, in turn, phosphorylates Katz et al. 2007). Of the multitude of signaling path- Raf and results in activation of downstream kinases ways, all ErbBs activate the Ras-MAPK upon ligand including MAP kinase kinases (MEK1/2). MEK1/2 binding (Figure 1). EGFR targets several members of subsequently phosphorylates ERK1/2 leading to the the MAPK family including extracellular regulated nuclear translocation of activated ERK where it initi- receptor kinases (ERK) ERK1/2, ERK5, janus kinases ates transcription of various genes including the speci- (JNK) and p38. Specifically, ERK1/2 is the most stud- ficity protein 1 (SP1), E2F, E twenty-six (ETS)-like ied and well characterized pathway activated by transcription factor 1 (ElK-1) and activator protein 1 growth factor receptors and associated with cell prolif- (AP-1). Gene transcription ultimately promotes cell eration (Katz et al. 2007). MAPKs are serine/threonine growth including proliferation, differentiation, migra- kinases that orchestrate key cellular functions includ- tion, invasion and anti-apoptosis. Recent studies have ing cell growth, differentiation and proliferation. described a new isoform of ERK, ERK5 that is linked MAPK pathways are activated either by direct recruit- to tumorigenesis and associated with cell proliferation. ment of the Src homology 2 (SH2) domain linked The in vivo animal studies support a critical role of growth factor receptor-bound protein 2 (Grb2) or indi- ERK5 in tumor growth due to the vasculogenesis and rectly by the phosphotyrosine-binding (PTB) domain. blood vessel homeostasis. Most importantly, tumor Grb2 then recruits son of sevenless (SOS), a nucleotide cells displaying high expression of ErbB2 also exhibit exchange factor further activating Ras, upon exchange elevated basal expression of ERK5 (Montero et al. of guanosine diphosphate (GDP) to guanosine triphos- Figure 1. Overview of the EGFR signaling pathway. Binding of EGF to EGFR leads to homo- and/or heterodimerization of
EGFR, phosphorylation and activation of MAPK (ERK/p38) and cell survival (PI3K/AKT) pathways. These pathways conse-
quently induce cell proliferation, invasion, and migration.
Journal of Molecular Biochemistry, 2013 110
In addition to MAPK pathways, the second most oncogenic pathway and focus of attention in tu- EGFR Directed Therapy in Breast Cancer
mor biology has been the PI3K/AKT (cell survival) EGFR and ErbB2 over-expression, phosphory- pathway (Yap et al. 2008). This pathway plays a cen- lation and heterodimerization are integral in tumor pro- tral role in cell proliferation, metabolism, growth and gression and therefore serve as important prognostic migration to overcome the deleterious and stressful factors for the development of therapeutic targets microenvironment in non-tumor cells (Vivanco & (Normanno et al. 2003). The main approach to control Sawyers 2002). Inappropriate PI3K signaling is typi- tumor growth is targeting ErbBs and its signal trans- cally associated with EGFR mediated tumor growth duction leading to inhibition of gene transcription. and failure in EGFR inhibition is linked with sustained Two strategies are commonly used for the treatment of PI3K signaling. There are three classes of PI3Ks, of ErbBs positive breast cancer; monoclonal antibodies which PI3K of class IA family are clearly activated by that block the membrane receptor upon binding to the growth factors including EGFR (Courtney et al. 2010, EC domain and small molecule tyrosine kinase inhibi- Kallergi et al. 2007a, Liang et al. 2006, Nicholson & tors (TKIs) that block the tyrosine kinase activity and Anderson 2002). Upon activation of EGFR, the p85 modulate downstream signaling pathways (Ciardiello catalytic subunit binds to the receptor tyrosine residues & Tortora 2001). and translocates PI3K to the plasma membrane The monoclonal antibody trastuzumab is the (Vivanco & Sawyers 2002). The membrane transloca- first line therapy for metastatic breast cancer and has tion of PI3K phosphorylates its substrate phosphatidy- been used clinically extensively (Goldenberg 1999). linositol (4,5)-bisphosphate (PIP2) to phosphatidy- Trastuzumab binds to the EC domain of the ErbB2 linositol (4,5)-trisphosphate (PIP3) and activates AKT receptor and inhibits the receptor phosphorylation, via binding to its upstream activator, phosphoinositide- thereby abrogating the tumor proliferation with better dependent kinase 1 (PDK1). AKT is the major down- outcome in breast cancer patients (Bozionellou et al. stream target of PI3K and upon activation leads to en- 2004). Randomized control trials have shown additive hanced cell growth and survival of tumors. Studies effects of trastuzumab with chemotherapy to reduce have shown that EGFR regulates the activity of cyclin the recurrence of disease by 50% and mortality by CD1, which induces cyclin dependent kinases that pro- >30%. An adjuvant therapy with paclitaxel (Taxol) in mote cell cycle progression. Activation of AKT down- 60-80% of breast cancer patients showed a promising regulates p27Kip1, an inhibitor of cyclin dependent outcome. Trastuzumab, in an adjunct therapy with kinases and regulates the cell cycle arrest (Vivanco & other anti-tumor agents such as aromatase inhibitor Sawyers 2002). Several genetic abnormalities are (anastrazole) have proven beneficial in ER/ErbB posi- marked by the hyperactivation of PI3K/AKT signaling tive breast tumors (Kaufman et al. 2009). Unlike tras- including the loss of PTEN, a tumor suppressor gene tuzumab, which binds to EC domain of ErbB2, Pertu- that dephosphorylates PIP3 to PIP2 hence shutting of zumab, a newly discovered monoclonal antibody, pre- the PI3K pathway (Courtney et al. 2010, Kallergi et al. vents ErbB2 homo- and heterodimerization with other 2007a, Liang et al. 2006, Nicholson & Anderson ErbBs, which is an important phenomenon seen in ag- gressive breast cancer tumors with shorter survival JAK-STAT pathway is also involved in EGFR rates (Kristjansdottir & Dizon 2010). Cetuximab, a mediated carcinogenesis. JAK belongs to the tyrosine chimeric human-mouse monoclonal antibody also kinases family that activates STATs (Darnell et al. binds to EGFR (Harding & Burtness 2005). Further- 1994). EGFR can mediate signaling via STATS by more, the complex of cetuximab-EGFR internalizes to different mechanisms, i.e, direct activation of STATs cause defective downstream signaling and inhibition of as well as by src-mediated EGFR signaling (Quesnelle cell proliferation leading to decreased invasiveness and et al. 2007). There are seven known members of the metastasis (Harding & Burtness 2005). STAT family: STAT1-4, STAT5a, STAT5b and In addition, several TKIs including gefitinib, STAT6. Upon activation by cytokines or growth fac- eroltinib and lapatinib are approved for clinical use tors, STATs undergo phosphorylation following asso- (Alvarez et al. 2010). Gefitinib and erlotinib are spe- ciation with JAK. Homo- or heterodimerization of cific EGFR inhibitors that bind to EGFR extracellu- STATs is a pre-requisite prior to their nuclear translo- larly and terminate the downstream signaling, pre- cation and induction of gene transcription. TGF-α or dominantly interfering with the ERK1/2 and PI3K/ EGF binding to EGFR is associated with activation of AKT signaling pathways (Campos 2008). Gefitinib is STAT-1, 3 and 5, in particular (Olayioye et al. 1999). a potent inhibitor of cell proliferation in tumors over-expressing EGFR. In phase I trials, gefitinib was well-tolerated with limited toxicities, mainly dermal and 111 Journal of Molecular Biochemistry, 2013
gastrointestinal (Herbst et al. 2002; Nakagawa et al. structural homology (Patel 1998, Reisine & Bell 2003). In patients with tamoxifen resistant breast tu- 1995). The transmembrane domains of SSTRs display mors, gefitinib showed anti-proliferative activity greater sequence homology than the extracellular N- (Baselga et al. 2005). Lapatinib, a reversible TKI, is terminal and intracellular C-terminal domains (Patel clinically used in breast tumors expressing both EGFR 1998). The pharmacological and physiological proper- and ErbB2. Interestingly, lapatinib binds to the mu- ties of SSTR in target tissues are subtype-specific. All tated or truncated forms of ErbB2 and exhibits an anti- SSTRs bind to SST-14 and SST-28 with nanomolar tumor effect (Bouchalova et al. 2010). A newly dis- affinities. The pharmacological profiles of receptors to covered TKI, neratinib is an irreversible inhibitor of ligand binding revealed that SSTR1-4 bind to SST-14 EGFR that has the ability to permanently abolish the while SSTR5 binds to SST-28 with greater affinity intracellular kinase activity of the receptor until a new (Patel 1998, 1999). receptor is synthesized and exhibits prolonged anti- tumor activity (Bose & Ozer 2009). Homo and/or Heterodimerization of SSTRs
The concept that GPCR exist and function in mono- Somatostatin and Somatostatin Receptors
meric entities has recently been challenged. The pres- The role of SST in the negative regulation of normal ence of multiple SSTR subtypes in the same cells in and tumor cell growth as well as the modulation of different tissues suggests the potential for dimerization growth factors and hormone mediated cell prolifera- between different SSTRs. Homo and/or heterodimeri- tion has emerged as a potential therapeutic approach zation of GPCRs within the same family has been well for tumor treatment (Pyronnet et al. 2008, Susini & documented (Baragli et al. 2007, Grant et al. 2004, Buscail 2006). The diverse biological effects of SST Heldin 1995, Jaquet et al. 2005, Jordan et al. 2001, are mediated through the interaction with the five spe- Rocheville et al. 2000a). Such protein-protein interac- cific receptors SSTR1-5. SSTRs were initially identi- tions are potential targets for new therapeutic agents. fied in rodent pituitary cells as high affinity cell sur- Rocheville et al. (2000b) were the first to report evi- face receptors (Schonbrunn & Tashjian 1978). The dence of physical interactions between SSTRs in trans- existence of more than one SSTR subtype was later fected cells. This study described that SSTR5 exists as proposed due to differential binding to SST-14 and a monomer in basal conditions and formed stable SST-28 (Mandarino et al. 1981, Srikant & Patel dimers upon SST treatment in a concentration depend- 1981). Based on their molecular cloning and binding ent manner. Patel et al. (2002) demonstrated an agonist properties, SSTRs were classified into two sub- dependent heterodimerization between SSTR1 and families; somatotropin release-inhibiting factor (SRIF) SSTR5, whereas SSTR5 formed homo and het- -1 and SRIF-2 (Patel 1998). The SRIF-1 class was erodimers. Unlike SSTR5, SSTR1 remained as a comprised of receptor subtypes sensitive to a specific monomer, irrespective of the agonist stimulation. Fur- ligand named OCT whereas receptors insensitive to thermore, the heterodimerization between SSTR1 and this ligand constituted the SRIF-2 class (Reisine & SSTR5 was subtype specific and was promoted by Bell 1995, Tran et al. 1985). SSTRs belong to the hep- SSTR5 activation alone (Patel et al. 2002). The swap- tahelical transmembrane GPCRs family and are high ping of SSTR5 C-tail with the C-tail of SSTR1 abro- affinity cell surface receptors (Schonbrunn & Tashjian gated the agonist mediated homodimerization and in- 1978). The sequence of human SSTRs was elucidated ternalization of SSTR5. Conversely, replacing the using molecular cloning techniques long after the SSTR1 with the SSTR5 C-tail, surprisingly, resulted identification of high-affinity plasma membrane SSTR in the chimeric receptor mimicking heterodimerization binding sites (Yamada et al. 1992, 1993). SSTR sub- and internalization of SSTR5 upon agonist stimulation. types have been cloned and are pharmacologically Grant et al. (2004) described that SSTR2 exists as pre- characterized in various species including humans formed dimers, which dissociate upon agonist treat- (Bruno et al. 1992, Kluxen et al. 1992, O'Carroll et al. ment prior to internalization. The same authors in a 1992). SSTR1 and SSTR2 were first cloned from hu- separate study also reported that SSTR2 activation se- man islets followed by cloning of SSTR3, SSTR4 and lectively promotes heterodimerization between SSTR5 in human as well as rat tissues (Yamada et al. SSTR2/5 whereas activation of SSTR5 alone or with 1992, 1993). Except SSTR2, the genes encoding SSTR2 failed to produce such heterodimerization. Fur- SSTRs are intronless (Patel 1999). SSTR2 gene ex- thermore, heterodimerization between SSTR2/5 modu- presses 2 splice variants; SSTR2A and SSTR2B, lates the signaling properties and was shown to have which differ in the number of amino acids in the C- an enhanced anti-proliferative effect. War et al. (2011) terminus. The size of SSTRs ranges from 356-391 demonstrated that SSTR3 exists as a pre-formed amino acid residues in length and exhibits 39-57% homodimer in the basal state whereas agonist treat- Journal of Molecular Biochemistry, 2013 112
ment decreases dimer formation. Additionally, C-tail mation, which further downregulates the protein kinase deficient SSTR3 displayed homodimerization similar A (PKA) pathway (Meyerhof 1998). The inhibitory to wt-SSTR3 (War et al. 2011). Similarly, SSTR4 ex- effect of SSTRs on the cAMP/PKA pathway has been ists as a dimer in monotransfected cells, however, demonstrated in human pituitary adenomas, rat cortex upon deletion of the C-tail, the receptor lost the ability and hippocampus, pancreatic islets as well as ovine to dimerize and displayed impaired internalization retina, in a receptor specific manner (Meyerhof 1998, (Somvanshi et al. 2009). Moreover, SSTR4 exhibited Patel 1999). SSTRs alter cGMP in a receptor and tis- receptor specific heterodimerization with SSTR5 but sue dependent manner, by modulating the activity of not with SSTR1 (Somvanshi et al. 2009). These stud- guanylyl cyclase, which also regulates nitric oxide me- ies established the critical role of the C-tail in receptor diated oxidative stress (Lahlou et al. 2004). Earlier dimerization and internalization and suggested that studies on rat pancreatic islets, human pituitary adeno- activation of one protomer is sufficient to promote re- mas and various other cell types have also demon- ceptor dimerization. Furthermore, SSTR2/3 het- strated that SSTRs modulate ion channels (Ca2+ and erodimers displayed high binding affinity to SST-14 K+) as well as phospholipase A (PLA) and phospholi- and SSTR2 specific agonist and resistance to agonist- pase C (PLC) pathways (Cervia & Bagnoli 2007, induced desensitization. Interestingly, SSTR2/3 het- Csaba & Dournaud 2001, Lahlou et al. 2004, Reisine erodimers were identified as new receptors, albeit with & Bell 1995). Additionally, SSTRs, via Gao2, regulate similar pharmacological properties as SSTR2 but with high-voltage gated Ca2+ channels and also inhibit intra- the loss of SSTR3-like properties (Pfeiffer et al. 2001). cellular Ca2+ entry in human pituitary adenomas, car- Heterodimerization of SSTRs within the same diac fibroblasts and cortical astrocytes as well as in rat family and with other related GPCRs is a well- sympathetic neurons, hippocampus and pancreatic established notion. SSTR2 functionally interact with µ- cells (Ikeda & Schofield 1989; Kleuss et al. 1991; Zhu opioid receptor in HEK-293 cells (Pfeiffer et al. 2002). & Yakel 1997). Concerning the specificity of the re- Furthermore, heterodimerization between SSTR5 and ceptor subtype, the involvement of SSTR2 has been dopamine receptor subtype 2 (D2R) and SSTR2/D2R studied in modulation of cAMP and Ca2+ whereas lim- opened an opportunity for the development of chimeric ited information is available on the roles of other sub- molecules targeting SSTR5/D2R that have been suc- types in this regard. Furthermore, SST has also been cessfully applied in the treatment of pituitary tumors suggested to activate conductance of different K+ (acromegaly) (Baragli et al. 2007, Jaquet et al. 2005, channels via SSTR4, leading to hyperpolarization of Saveanu et al. 2002). Recent studies showed that syn- the cell membrane in human and rat brain regions as ergistic activation strengthened the pre-existing SSTR5 well as pituitary and pancreatic cells (de Weille et al. and β-adrenergic heterodimers whereas activation of 1989). The effects of SST on the Na+/H+ pump have individual receptor subtypes leads to the dissociation been studied in rat hepatocytes as well as breast cancer of the heteromeric complex (Somvanshi et al. 2011). cells of different origins and are mainly mediated via The heterodimerization of SSTRs has been shown to SSTR2 and SSTR5. enhance the signaling properties and such functional consequences may have potential therapeutic implica- SSTRs and Breast Cancer
tions in different pathological states. SST and SSTRs are highly expressed by breast cancer Molecular Signaling of SSTRs
cells and autopsied breast tissue. SSTl immunoreactiv- Ligand binding to SSTRs initiates complex signal ity has been demonstrated in approximately 30% of transduction pathways (Figure 2). Agonist mediated breast tumor tissues as well as in most breast cancer activation of SSTRs leads to conformational changes cell lines (Albérini et al. 2000, Kumar et al. 2005, in the receptor prior to coupling with the G-proteins Reubi 1990, Weckbecker et al. 1994). As discussed comprised of a trimeric complex of three tightly bound above, there are direct and indirect mechanisms for the subunits (α, β and γ). Upon activation, G-proteins con- SST effects on breast tumor cells. The direct effect of vert GDP to GTP by nucleotide exchange and conse- SST or its analogs is exerted by binding to SSTRs, quently relay downstream signals via dissociation of resulting in inhibition of cell proliferation and/or in- the α subunit from the βγ complex (Pierce et al. 2002). duction of apoptosis. Studies have demonstrated that Adenylyl cyclase (AC) was among the first identified 15-66% of primary breast tumors are positive for enzyme effectors regulated by GPCRs, including SSTRs by binding analysis whereas 75% were posi- SSTRs (Patel et al. 1994). All SSTR subtypes bind to tive when imaged in vivo using [111In-DTPA-DPhe1] pertussis toxin (PTX) sensitive G-proteins that are Gi/o -octreotide scintigraphy (Prevost et al. 1994, Weck- type and negatively regulate AC to inhibit cAMP for- becker et al. 1994). Pfeiffer et al. (2002) demonstrated 113 Journal of Molecular Biochemistry, 2013
that SSTR2 and SSTR5 were the predominant sub- Vikic-Topic et al., the findings by Kumar et al. (2005) types expressed in these tumors. Several previous established the correlation of SSTRs with the tumor studies have also reported that SSTR2 is the most grade and the levels of ER and PR. SSTR1 and 4 were abundant SSTR subtype expressed in breast tumors correlated with ER whereas SSTR2 was correlated (Evans et al. 1997, Kumar et al. 2005, Reubi et al. with PR in addition to ER. 1990, Watt & Kumar 2006). In addition, SSTR2 ex- In the past few years, various SST analogs pression has been found to be ubiquitous (Evans et al have been developed and used as anti-proliferative 1997). Vikic-Topic et al. (1995) described that the agents in the treatment of breast cancer. Unlike SST SSTR2 transcript is predominantly expressed in all that has a short plasma half-life of 3 minutes, newly breast tissue samples, followed by SSTR1, SSTR3 and synthesized SST analogs have better efficacy, thera- SSTR4. Moreover, SSTR1 was detected along with peutic index and are free from major side effects SSTR2 transcripts in 96% of breast tissues examined. (Lamberts et al. 1991, Schally 1988). Setyono-Han et Furthermore, the expression of mRNA and protein al. (1987) showed the inhibitory effects of Sandostatin levels of all SSTR subtypes was shown in a cumula- (an analog of SST) on proliferation of MCF-7 cells in tive study of 98 ductal not otherwise specified (NOS) a concentration and time dependent manner. Interest- breast tumor cases (Kumar et al. 2005). Additionally, ingly, Sandostatin had an antagonizing effect on estra- it was suggested that the SSTRs are variably distrib- diol and growth hormones in MCF-7 cells suggesting uted at the tumor site and adjacent tumor regions that SST and SST analogs directly act as potential anti (Kumar et al. 2005). In contrast to observations by -proliferative agents on human breast cancer cells. Figure 2. Schematic illustration of SSTR signaling. Activation of SSTRs by SST or receptor-specific agonists inhibits Ca2+
influx and hormonal secretions. SSTRs couple to Gi proteins and commonly inhibit cAMP. SSTRs modulate the MAPK and
PI3K pathways in a receptor specific manner and result in inhibition of cell proliferation, survival and migration.
Journal of Molecular Biochemistry, 2013 114
Vapreotide, another SST analog, was evaluated and it SSTR and ErbB subtypes are extensively expressed in was found that prolonged administration was well tol- breast tissues and cell lines (Kumar et al. 2005, Rivera erated in cases of pre-treated metastatic patients, re- et al. 2005, Watt & Kumar 2006). SSTRs and ErbBs sulting in diminished levels of IGF-1 during the entire are co-expressed in breast cancer cells and display length of the treatment (O'Byrne et al. 1999). Simi- colocalization in a receptor, cell line and ER- larly, Canobbio et al. (1995) indicated that the SST dependent manner. SSTR subtypes are highly ex- analog Lanreotide significantly suppressed the levels pressed in ER- cells, whereas these cells expressed of IGF-1 in postmenopausal breast cancer patients relatively low levels of ErbBs in comparison to ER+ previously untreated for the tumor. cells (Watt and Kumar 2006). SST also inhibits the Amongst all SST analogs, octeriotide (OCT) effects of EGF in pancreatic tumors, indicating that has been studied extensively for the treatment of dif- activation of SSTR subtypes may impede ErbBs het- ferent types of tumors. As an anti-hormonal drug, erodimerization and diminish its tumor promoting ef- OCT has been used in combination with tamoxifen for fects (Liebow et al. 1986). In addition, SSTRs and the treatment of breast cancer as well as in DMBA- ErbBs regulate the MAPK and PI3K/AKT pathway in induced rat mammary carcinoma. OCT also effec- a receptor specific manner; albeit, with opposite out- tively increased the anti-neoplastic effect of ovariec- comes on cell proliferation. tomy in these rat models (Weckbecker et al. 1994). Sharma et al. (1996) demonstrated that SST had a cy- SSTRs Modulate EGFR Functions
totoxic effect on MCF-7 cells in a receptor-specific SSTR1 and SSTR5 modulate EGFR heterodimeriza- manner. In this regard, it should be noted that SSTR3 tion and tumor promoting downstream signaling in is the only receptor subtype that uniquely participates breast cancer as well as HEK-293 cells (Watt et al. in the induction of apoptosis. Furthermore, OCT in- 2009, Kharmate et al. 2011a, b) (summarized in Fig- duced apoptosis through activation of tumor suppres- ure 3). In breast cancer cells, agonist treatment re- sor proteins, namely wild-type 53 and Bcl-2– sulted in the dissociation of SSTR5/EGFR and the associated X protein (Bax) in MCF-7 cells, suggesting association of SSTR1/EGFR. The agonist dependent a potential antitumor role of SST analogs (Sharma & association/dissociation between SSTRs/EGFR conse- Srikant 1998). Paclitaxel, known for its excellent anti- quently led to the modulation of ERK1/2 phosphoryla- tumor activity lacks cell specificity. Huang et al. tion. Watt et al. (2009) demonstrated that there is a (2000) synthesized an OCT conjugated with paclitaxel synergistic activation of SSTR and EGFR upon treat- that internalized into the cytoplasm of SSTR positive ment with SST and EGF which delayed the phos- tumor cells and induced apoptosis in MCF-7 cells by phorylation of ERK1/2 in MCF-7 cells, suggesting a promoting tubule formation, while retaining pacli- mechanism whereby SST can block EGF-induced pro- taxel's biological properties. liferation. These results further strengthen the concept that SSTRs and ErbBs functionally interact in cancer. Cross-talk between ErbBs and SSTRs
The concept that SSTR and ErbB receptors EGFR has been associated with cell proliferation, sur- associate as heterodimers or possibly display ligand- vival and transformation (Normanno et al. 2006). In dependent dissociation of preformed heteromeric com- pathological conditions such as breast cancer, ErbBs plexes with significant changes in signaling molecules are highly expressed in higher grade and aggressive has enormous implications for receptor biology in can- tumors. SSTRs are known to be negative regulators of cer and in drug development. Kharmate et al. (2011a, cell proliferation and have been acknowledged for the b) demonstrated that the presence of SSTR1 or 5 al- treatment of various tumors (Bousquet et al. 2004, tered EGFR membrane expression, phosphorylation Cameron Smith et al. 2003, Patel 1990). Unlike and heterodimerization of EGFR/ErbB2. EGFR het- ErbBs, SSTRs are well expressed in lower grade and erodimerization with ErbB2 and receptor phosphoryla- less aggressive breast tumors. These observations sug- tion are critical steps in stimulating and sustaining the gest an inverse relation between SSTR and ErbB sub- downstream cell proliferating signals linked to tumor types in breast cancer. Finding that activation of growth. The activation of SSTR 1 or 5 in transfected GPCRs leads to the phosphorylation of EGFR result- HEK-293 cells significantly diminished the membrane ing in enhanced and diversified signaling established expression of EGFR, which was consistent with the the first paradigm of inter-receptor crosstalk. Daub et observations in breast cancer cells. SSTR5 alone and al. (1996) were the first to describe the concept of in combination with SSTR1 partially blocked EGFR EGFR transactivation by GPCRs in rat fibroblasts. phosphorylation (Kharmate et al. 2011a, b). In com- There is compelling evidence that could substantiate parison, SSTR1 monotransfected cells completely the possible crosstalk between SSTRs and ErbBs. All abolished EGFR phosphorylation. Furthermore, in wt- 115 Journal of Molecular Biochemistry, 2013
HEK-293 cells, while EGF enhanced the ERK1/2 and 5 specifically induced cytostatic rather than cyto- phosphorylation in a time dependent manner, SST toxic effects (Kharmate et al. 2011a, b). alone or in combination with EGF showed comparable PI3K/AKT cell survival pathways play an im- ERK1/2 phosphorylation. Interestingly, in SSTR1 or portant role in tumor progression. Aggressive tumor SSTR5 expressing cells, EGF induced ERK1/2 phos- growth is frequently associated with the loss of PTEN, phorylation was significantly less, whereas upon con- a hyperactivated PI3K pathway and the failure of comitant treatment of SST and EGF, ERK1/2 phos- Trastuzumab therapy (Kallergi et al. 2008). Further- phorylation was prolonged. Furthermore, activation of more, the activation of SSTR1 or 5 lead to the inhibi- SSTR1 or 5 in mono- and/or cotransfected cells modu- tion of PI3K and AKT phosphorylation. Moreover, late EGF mediated ERK5 phosphorylation. Of note, this inhibition was shown to be more pronounced in SST displayed a much greater inhibitory effect on cells expressing SSTR1/5 indicating that SSTRs acti- EGF mediated ERK1/2 and ERK5 phosphorylation in vation might play a role in response to Trastuzumab SSTR1/5 cotransfected cells. Similarly, SSTRs inhibit treatment in cancer. It is highly possible that the grad- EGF mediated p38 phosphorylation in a receptor spe- ual loss of SSTR subtypes as the tumor progresses cific manner with pronounced inhibition in the pres- might, in part, be responsible for the loss of Trastuzu- ence of SSTR1 alone. Furthermore, these results were mab responsiveness, being associated with enhanced corroborated with the changes in the expression levels PI3K and loss of PTEN. Kharmate et al. (2011a, b) of p27kip1, an index of cell proliferation and PTP mem- demonstrated that cells expressing SSTR1, SSTR5 and brane translocation. These results suggest that SSTR1 SSTR1/5 promote the dissociation of the EGFR/ Figure 3. SSTRs modulate EGF mediated signaling pathways. Activation of SSTRs inhibits the EGF-mediated EGFR homo-
and/or heterodimerization, receptor phosphorylation as well as the MAPK and PI3K/AKT pathways, resulting in inhibition of
cell proliferation.
Journal of Molecular Biochemistry, 2013 116
ErbB2 heteromeric complex. SSTR1 and SSTR5 monotransfected cells exhibited SSTR1/EGFR or SSTR5/ EGFR heteromeric complex formation, result- This work was supported by the Canadian Institute of ing in the inhibition of EGFR phosphorylation. More Health Research Grant (MOP 10268 and MOP importantly, SSTR1/5 cotransfected cells displayed 74465), a grant from the Canadian Breast Cancer SSTR5/EGFR heterodimerization whereas there was Foundation BC/Yukon and NSERC to UK. UK is a no SSTR1/EGFR complex formation. These observa- Senior Scholar of Michael Smith Foundation for tions show that the interference of SSTRs in the ErbB Health Research. homo- and/or heterodimerization, the consequent inhi- bition of EGFR phosphorylation and the regulation of Author's Contributions
EGF-mediated downstream signaling might serve as novel therapeutic targets in EGFR positive tumors. GK and UK designed and drafted the article. Both au- Most importantly, inhibition of EGFR using AG1478 thors read and approved the final manuscript. and knocking down EGFR in the presence of siRNA enhanced SSTR1 and SSTR5 mediated inhibition of References
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