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Estrogen signaling and unfolded protein response in breast cancer
Accepted Manuscript Title: Estrogen signaling and unfolded protein response in breast cancer ˚ Author: Gayani Rajapaksa Christoforos Thomas Jan-Ake Gustafsson PII: DOI: Reference:
S0960-0760(16)30093-0 http://dx.doi.org/doi:10.1016/j.jsbmb.2016.03.036 SBMB 4690
To appear in:
Journal of Steroid Biochemistry & Molecular Biology
Received date: Revised date: Accepted date:
18-1-2016 11-3-2016 31-3-2016
˚ Gustafsson, Please cite this article as: Gayani Rajapaksa, Christoforos Thomas, Jan-Ake Estrogen signaling and unfolded protein response in breast cancer, Journal of Steroid Biochemistry and Molecular Biology http://dx.doi.org/10.1016/j.jsbmb.2016.03.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Estrogen signaling and unfolded protein response in breast cancer
Gayani Rajapaksa, Christoforos Thomas, Jan-Åke Gustafsson
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA
Correspondence to Christoforos Thomas, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA; [email protected] Jan-Ake Gustafsson, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA; [email protected]
Highlights
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UPR correlates with therapy resistance in breast cancer.
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Estrogen activates all three arms of the UPR in ERα-positive tumors.
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ERα mediates a cytoprotective UPR that assists tumors to resist therapy.
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Regulation of the UPR is a new role for ERβ in breast cancer.
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Therapies with ER ligands that decrease protective UPR signaling are being tested.
Abstract Activation of the unfolded protein response (UPR) confers resistance to anti-estrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers. Among the regulators of the UPR in breast cancer is estrogen signaling. Estrogen regulates major components of the UPR and ER expression is associated with the sensitivity of tumor cells to UPR-regulated apoptosis. Recent studies have confirmed the crosstalk between the ERs and UPR and suggest novel therapeutic strategies that combine targeting of both signaling pathways. These remedies may be more effective in repressing oncogenic adaptive mechanisms and benefit patients with resistant disease.
Keywords: nuclear receptors, steroid hormone, estrogen
Introduction
Despite recent advancements in methods of detection and novel treatment approaches, approximately 40,000 breast cancer-associated deaths are predicted to occur in the United States in 2015 [1]. The high mortality rates are associated with the limited number of prognostic markers and therapeutic targets [2, 3]. Nearly 70% of breast tumors express estrogen receptor α (ERα) suggesting the use of anti-estrogens as standard treatment option for hormonedependent breast cancer. Treatment with the selective estrogen receptor modulator (SERM) tamoxifen, which acts as an ERα antagonist in breast, has been shown to reduce breast cancer mortality by one-third. However, not all breast cancers respond to endocrine therapy [4]. Chemotherapy is currently the only viable treatment option for triple-negative breast cancers (TNBCs) that are typically negative for ERα, progesterone receptor and human epidermal growth factor receptor 2 (HER-2). However, patients with TNBC tend to relapse with metastases [5]. Several mechanisms of resistance to endocrine therapy and chemotherapy have been proposed in breast cancer. These include the presence of ERα mutations, aberrant activity of co-regulatory proteins, constitutive activation of growth factor receptors, downregulation of proapoptotic signaling pathways, alteration in DNA response process and upregulation of prosurvival autophagy [6, 7]. By modulating such processes, tumor microenvironment has been suggested to contribute to anti-estrogen and chemotherapy resistance in breast and other types of cancer. Microenvironment conditions such as hypoxia and nutrient deprivation modulate prosurvival and pro-apoptotic signaling pathways by inducing stress and activating adaptive responses in tumor cells [8-10]. Hypoxia and nutrient deprivation in tumor microenvironment perturb the process of protein folding and induce stress in the endoplasmic reticulum (EnR) of cancer cells. Accumulation of unfolded proteins in the EnR sets off a series of adaptive mechanisms that together are known as unfolded protein response (UPR). UPR restores EnR homeostasis by
adjusting the protein folding capacity of the EnR and various other processes such as metabolism, energy production and cell differentiation [11]. UPR usually protects the cells from EnR stress, however, when severe or prolonged EnR stress cannot be mitigated, UPR eliminates stressed cells by apoptosis [12]. Activation of the UPR has been associated with therapy resistance and recurrence in breast cancer [10, 13]. The first evidence showing regulation of the EnR stress response by estrogen signaling in malignant breast was provided two decades ago [14]. The association of the two signaling pathways has been corroborated in several studies including those that have recently implicated both estrogen receptors in the regulation of the response [15, 16]. Estrogen impacts all three UPR pathways by regulating major transducers such as glucose regulated protein 78 (GRP78) and X-box binding protein-1 (XBP-1) that are upregulated in endocrine- and chemotherapy-resistant breast cancers [15, 17-24]. However, the impact of the hormone on UPR may vary in different breast cancer cell types depending on their context. In this review, we will provide insights into the mechanisms underlying the association of estrogen with the UPR signaling in breast cancer. We will also discuss how this crosstalk could lead to development of novel strategies to effectively regulate both signaling pathways and benefit patients with recurrent disease. Unfolded protein response EnR is the major compartment for folding of secretory and transmembrane proteins [25]. The process of protein folding is sensitive to alterations in rate of protein synthesis, glucose, oxygen and Ca2+ levels as well as redox imbalance and the presence of pathogens. These conditions lead to accumulation of unfolded proteins in the EnR lumen which is known as EnR stress. To cope with the EnR stress, cells activate the UPR which transiently decreases the rate of protein synthesis, increases the capacity of protein folding and reduces the overload of misfolded proteins through EnR-associated degradation (ERAD) and autophagy [11, 26-28]. In the
absence of misfolded proteins, the chaperone GRP78 binds to and prevents the activation of the EnR transmembrane proteins EnR-localized transmembrane protein inositol requiring enzyme 1 (IRE1), double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). Upon induction of EnR stress, GRP78 dissociates from its normal substrates to bind to unfolded proteins in the EnR lumen allowing the activation of the three UPR transducers [11]. Activation of PERK inhibits general protein synthesis through inactivation of the translation initiation factor eIF2α. Expression of the activating transcription factor ATF4 escapes the global translation block and promotes a gene expression program that regulates amino acid and redox metabolism, apoptosis and autophagy [11, 27, 29]. Activated IRE1 splices the mRNA that encodes the transcription factor XBP-1. This results in the expression of a strong transcription factor known as spliced XBP-1 (XBP-1s) that induces genes that promote protein folding and ERAD [30]. Another UPR pathway is initiated by the activation of ATF6. This occurs when ATF6 processing at Golgi produces a transcriptional activator that executes a pro-survival gene expression program [31, 32]. In addition to EnR, perturbation of the folding environment that leads to accumulation of misfolded proteins has been described in mitochondria [33]. Activation of mitochondrial UPR has been suggested to reduce proteotoxic stress in the organelle by upregulating nuclear genes that encode mitochondrial chaperones and proteases. Central role in the activation of this response in mammalian cells plays the transcription factor CHOP [34]. However, the precise mechanisms that sense the stress and activate the transducers of the mitochondrial UPR are poorly understood. Moreover, the relation of the response to cancer has not been established. While activation of the UPR in EnR restores physiological responses in various tissues, its aberrant activation has been detected in pathological conditions including metabolic disorder, inflammation, neurodegeneration, autoimmunity and cancer [11, 35]. Due to higher mitotic,
metabolic and in some tissues secretory activity, tumor cells require increased rate of protein synthesis that leads to alterations in protein folding and activation of the UPR. Similarly, UPR activation is observed in immune and endothelial cells of tumor stroma due to their increased synthesis and secretion of growth factors. In addition, cancer cells activate the UPR because they usually grow in hypoxic and hypoglycemic environment that disturbs protein folding [36]. Estrogen signaling and unfolded protein response in breast cancer Among the tissues with high secretory activity is the mammary gland. Estrogen regulates cell differentiation, proliferation and apoptosis that occur during lactation/involution cycles in normal mammary gland [37]. Estrogen signaling cooperates with the UPR to assist mammary cells to cope with the EnR stress that is induced during the synthesis and secretion of milk proteins [38]. The crosstalk between estrogen and UPR represents a dynamic signaling that is utilized by the neoplastic breast to adopt to stress in tumor microenvironment due to inadequate vascularization or the application of cytotoxic and endocrine therapies [10, 39, 40]. Endocrine is the standard therapy for patients with ERα-positive disease. However, intrinsic resistance to the anti-estrogen tamoxifen is seen in 50% of advanced ERα-positive tumors and as many as 40% of tamoxifen-treated cancers develop acquired resistance [10, 41]. Similar to ERα-positive disease, the majority of patients with TNBC tend not to respond to chemotherapy and develop resistant disease [42]. A growing body of evidence suggests that UPR regulates cell survival and apoptosis in breast tumors and determines their response to endocrine therapies and chemotherapies [10, 19, 23, 43]. Activation of the UPR in response to estrogenic stimulation was initially observed in the 90’s when 17β-estradiol was shown to protect ERα-positive breast cancer cells from thermal injury by inducing the expression of the heat shock protein 70 family member and UPR regulator GRP78 [14]. Several studies using cell-based and xenograft models have validated the UPR as one of the mechanisms employed by estrogen to regulate oncogenic responses in breast tumor
cells [15, 16, 38]. Estrogen induces the expression of the UPR components XBP-1 and GRP78 [23, 24, 44]. GRP78 and XBP-1 are overexpressed in 60-70% and 80-90% of breast tumors, respectively [3, 19, 22-24, 43, 45, 46]. Higher expression of XBP-1 mRNA was found in ERαpositive compared with the ERα-negative tumors suggesting that UPR is regulated by estrogen receptor [47]. This was further supported by the correlation of XBP-1 and GRP78 expression with that of ERα in breast tumors [23, 48]. High expression of XBP-1 and GRP78 was observed in anti-estrogen-resistant breast cancer cells in vitro [49] and endocrine-resistant breast tumors [2, 17, 18, 21, 50]. ERα and unfolded protein response in breast cancer Laboratory and clinically based studies have associated the UPR with ERα and endocrine therapy in breast cancer. XBP-1 was initially predicted as a key gene in an expression network that is associated with anti-estrogen resistance [51]. Correlation of XBP-1 with endocrine resistance was also observed in clinical breast cancer specimens during gene expression analysis [20, 48]. In addition to XBP-1, a UPR-associated gene expression signature has recently been identified as a powerful prognostic marker that predicts tamoxifen resistance in ERα-positive breast cancers. The same signature has also been associated with reduced time to recurrence and poor survival in the same breast cancer phenotype [15]. In addition to endocrine resistance, XBP-1 positivity was correlated with ERα expression in luminal breast cancers [2, 3]. More recently, by applying DNA microarray analysis several independent groups have identified XBP-1 as an estrogen responsive gene within the luminal cluster and an important feature of the gene expression signature that defines the luminal phenotype [52-54]. The clinical indication of XBP-1 as an estrogen responsive gene was corroborated in breast cancer cell-based studies. Estrogen-dependent regulation of XBP-1 expression was first observed by Finlin and colleagues and was subsequently validated by other groups [24, 44, 52, 53, 55]. Regions of the XBP-1 gene were identified among the ERα-regulated promoters
suggesting a potential regulation of XBP-1 transcription by estrogen and ERα [44]. Chromatin immunoprecipitation followed by microarray confirmed the recruitment of ERα on the promoter of XBP-1 gene [56]. More recently, Sengupta and colleagues have further corroborated the regulation of XBP-1 by estrogen and ERα and associated the upregulation of XBP-1 with estrogen-induced growth of ERα-positive breast cancer cells [24]. In addition to its identification as an estrogen responsive gene, XBP-1 was reported to regulate the expression and promote ligand-independent activation of ERα [56-59]. The transcriptional output of the ERα-XBP-1 cooperation may account for the decreased sensitivity of tumors that express both proteins to endocrine therapy [2, 3, 23, 50, 60, 61]. Indeed, coexpression of both unspliced and spliced forms of XBP-1 with full length-ERα correlates with enhanced ERα transcriptional activity in breast cancer cells. This is because ERα physically interacts with XBP-1 in a ligand-independent manner. The N-terminus of XBP-1 is indispensable for the interaction and essential for the effect of XBP-1 on ERα function [58]. The transcriptional complex involves another ERα co-activator, the steroid receptor co-activator 1 (SRC-1). SRC-1 cooperates with XBP-1 to promote large scale chromatin unfolding and increase the activity of the receptor [58, 59]. As a result, XBP-1s drives E2-independent activation of ERα and is more potent than the hormone in activating the receptor. In addition, XBP-1 potentiates the effects of estrogen on estrogen-dependent transcription in vitro [58]. The XBP-1-dependent activation of ERα enables estrogen-independent breast cancer cell growth. It also reduces the sensitivity of cells to the growth inhibitory effects of anti-estrogens both in vitro and in vivo [57]. Consistent with the cell growth effects, XBP-1s was found to regulate genes associated with apoptosis, cell cycle and estrogen responsiveness in ERα-positive breast cancer cells [57]. XBP-1s prevents cell cycle arrest and anti-estrogen-induced cell death by inhibiting the mitochondrial apoptotic pathway [57]. GRP78 is another estrogen-regulated UPR component that is overexpressed in human breast tumors [17, 23]. By upregulating pro-survival autophagy and inhibiting apoptosis, GRP78
contributes to endocrine resistance in ERα-positive breast cancers [17]. In response to EnR stress GRP78 activates all major UPR transducers and estrogen was found to upregulate all three arms of the UPR in ERα-positive breast cancer cells both in vitro and in vivo [15]. ERαdriven mild and transient UPR activation sustains cell survival and proliferation during EnR stress imposed by endocrine therapeutic interventions (Fig. 1). This may account for the decreased tamoxifen sensitivity of ERα-positive breast tumors that overexpress UPR-associated genes [15]. The prosurvival transient UPR activation in ERα-positive cells seems to be disrupted by the selective inhibition of ERα. In the presence of estrogen, BHPI, a potent noncompetitive ERα modulator has recently been found to promote a prolonged and pro-apoptotic UPR signaling that decreases the survival of endocrine-resistant breast cancer cells and induces tumor regression in a mouse model of breast cancer [15]. Thus, small molecules that inhibit ERα function and lead to irreversible activation of the UPR may represent novel therapeutics to overcome resistance in breast cancer [62]. Interestingly, similarly to EnR, ERα has been reported to mediate a cytoprotective UPR in mitochondria. Accumulation of unfolded proteins in mitochondria leads to estrogenindependent activation of ERα in breast cancer cells. In turn, activated ERα induces a gene expression program that increases the activity of proteasome to limit the accumulation of unfolded proteins and protect the integrity of the organelle [63]. Regulation of the unfolded protein response by ERβ While ERα promotes cell proliferation, anti-proliferative and anti-invasive responses have been observed following upregulation of wild-type ERβ in breast cancer cell lines [64-67]. Correlations between the expression of ERβ and clinical outcome have been explored in several studies. The majority of the studies examining patients with ERα-positive tumors have indicated that increased expression of wild-type ERβ (ERβ1) correlates with a more favorable response to endocrine therapy [68-70]. In patients with TNBC, ERβ1 expression has consistently been
associated with increased survival [70-72]. Several mechanisms to explain the tumor repressive actions of the receptor have been proposed. Among these, network modeling predicted a potential association of ERβ with the network topology of the UPR component [10]. However, the role of the receptor in the UPR signaling has not been experimentally studied until very recently when ERβ1 was reported to activate EnR stress-regulated cell death pathways [16]. In response to treatment with pharmacological EnR stress inducers, upregulation of ERβ1 or treatment with ligands that activate the receptor decreased the survival and enhanced apoptosis in both anti-estrogen sensitive and –resistant breast cancer cells. Upon EnR stress, ERβ1 downregulated the IRE1α and decreased the splicing and the activity of XBP-1 (Table 1). This effect was observed in ERα-positive and TN breast cancer cells suggesting the involvement of both ERα-dependent and -independent mechanisms. Given that XBP-1 drives progression in TNBC [19], the inhibitory effect of ERβ1 on UPR in TNBC cells may account for the previously described
association of
the
receptor
with
decreased
invasiveness
and
increased
chemosensitivity of TNBC cells [66, 73]. In addition, given that bortezomib is tested in clinical trials for treatment of metastatic breast cancer [74], the pro-apoptotic ERβ1 function in bortezomib-treated metastatic cells may suggest the combined use of ERβ agonists and bortezomib as an effective remedy for patients with metastatic disease. In contrast to wild-type isoform, the splice variant ERβ2 (also known as ERβcx) which differs from ERβ1 in 26 Cterminal amino acids did not alter XBP-1 activity and the sensitivity of breast cancer cells to EnR stress inducers [16]. The different effect of ERβ isoforms on UPR may account for their different associations with the clinical outcome in breast cancer patients [75]. Concluding remarks Activation of the UPR in breast cancer correlates with therapeutic resistance and worse clinical outcome. Targeting proximal UPR components that are often overexpressed in neoplastic breast has a great potential for breast cancer treatment. Several compounds have been
identified and are currently being tested in preclinical models and clinical settings [76]. Given that the UPR cooperates with other oncogenic factors to drive breast cancer progression, strategies that target more pathways seem to be more effective in combating resistant disease. Co-expression of XBP-1 and ERα in luminal phenotypes, the ligand-independent activation of ERα by XBP-1 and the activation of the cytoprotective UPR signaling by the receptor represent modes of UPR-estrogen signaling combined action that may drive estrogen independency and anti-estrogen resistance (Table 1). Thus, endocrine resistant tumors may benefit from a concomitant manipulation of the UPR and estrogen receptor activity. However, the ER subtypespecific expression changes in breast cancer and the distinct effects of ERs and their variants on UPR suggest selective targeting of estrogen signaling with ER subtype-specific ligands. The rationale of therapeutic strategies that intend to decrease protective UPR signaling responses through both UPR and ER subtype-selective targeting warrants further investigation. Future studies should clarify the specific effects of ER subtypes and their variant isoforms in various cytoprotective and pro-apoptotic UPR pathways as well as how different ER ligands affect the UPR responses.
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Figures Figure 1. Proposed mechanism illustrating the regulation of the UPR by estrogen receptors in breast cancer. Induction of EnR stress leads to activation of UPR transducers IRE1α, PERK and ATF6. PERK activation promotes cell survival by inhibiting global protein synthesis. Active IRE1α promotes splicing of XBP1 mRNA. This results in the generation of the transcription factor XBP-1s that induces the expression of cell survival genes. ERα upregulates all three arms of the UPR. ERα can promote cell survival by directly inducing the expression of XBP-1. In addition, XBP-1 binds to and activates ERα in the absence of estrogen. The interaction of ERα with XBP-1 leads to activation of a gene expression program that promotes endocrine resistance. In contrast, by downregulating IRE1α, ERβ1 decreases the expression of pro-survival XBP-1s and enhances EnR stress-regulated apoptosis.
Table 1. Effects of estrogen and estrogen receptors on UPR
ER ligands
Estrogen/ERα agonists activate the IRE1, PERK and ATF6 pathways
[14, 15, 17, 22-24, 44, 49, 52, 53, 55, 57]
ERβ agonists decrease XBP-1 activity
[16]
ERα activates the IRE1, PERK and ATF6 pathways
[15, 62]
Association between XBP-1 and endocrine resistance
[51]
XBP-1 is co-expressed with ERα in luminal tumors
[2, 3, 52-54]
High expression of XBP-1 in ERα-positive breast cancer
[2, 3, 18, 21, 23, 24, 44, 47,
XBP-1 interacts with ERα
[56-59]
GRP78 is overexpressed in ERα-positive breast cancers
[17, 18, 23]
Predicted association between XBP-1 and ERβ
[10]
ERβ1 downregulates the IRE1/XBP-1 pathway
[16]
ERα
ERβ
48, 50, 60, 61]
S0960-0760(16)30093-0 http://dx.doi.org/doi:10.1016/j.jsbmb.2016.03.036 SBMB 4690
To appear in:
Journal of Steroid Biochemistry & Molecular Biology
Received date: Revised date: Accepted date:
18-1-2016 11-3-2016 31-3-2016
˚ Gustafsson, Please cite this article as: Gayani Rajapaksa, Christoforos Thomas, Jan-Ake Estrogen signaling and unfolded protein response in breast cancer, Journal of Steroid Biochemistry and Molecular Biology http://dx.doi.org/10.1016/j.jsbmb.2016.03.036 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Estrogen signaling and unfolded protein response in breast cancer
Gayani Rajapaksa, Christoforos Thomas, Jan-Åke Gustafsson
Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA
Correspondence to Christoforos Thomas, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA; [email protected] Jan-Ake Gustafsson, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, 3605 Cullen Blvd, Houston, Texas 77204, USA; [email protected]
Highlights
•
UPR correlates with therapy resistance in breast cancer.
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Estrogen activates all three arms of the UPR in ERα-positive tumors.
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ERα mediates a cytoprotective UPR that assists tumors to resist therapy.
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Regulation of the UPR is a new role for ERβ in breast cancer.
•
Therapies with ER ligands that decrease protective UPR signaling are being tested.
Abstract Activation of the unfolded protein response (UPR) confers resistance to anti-estrogens and chemotherapeutics in estrogen receptor α (ERα)-positive and triple-negative breast cancers. Among the regulators of the UPR in breast cancer is estrogen signaling. Estrogen regulates major components of the UPR and ER expression is associated with the sensitivity of tumor cells to UPR-regulated apoptosis. Recent studies have confirmed the crosstalk between the ERs and UPR and suggest novel therapeutic strategies that combine targeting of both signaling pathways. These remedies may be more effective in repressing oncogenic adaptive mechanisms and benefit patients with resistant disease.
Keywords: nuclear receptors, steroid hormone, estrogen
Introduction
Despite recent advancements in methods of detection and novel treatment approaches, approximately 40,000 breast cancer-associated deaths are predicted to occur in the United States in 2015 [1]. The high mortality rates are associated with the limited number of prognostic markers and therapeutic targets [2, 3]. Nearly 70% of breast tumors express estrogen receptor α (ERα) suggesting the use of anti-estrogens as standard treatment option for hormonedependent breast cancer. Treatment with the selective estrogen receptor modulator (SERM) tamoxifen, which acts as an ERα antagonist in breast, has been shown to reduce breast cancer mortality by one-third. However, not all breast cancers respond to endocrine therapy [4]. Chemotherapy is currently the only viable treatment option for triple-negative breast cancers (TNBCs) that are typically negative for ERα, progesterone receptor and human epidermal growth factor receptor 2 (HER-2). However, patients with TNBC tend to relapse with metastases [5]. Several mechanisms of resistance to endocrine therapy and chemotherapy have been proposed in breast cancer. These include the presence of ERα mutations, aberrant activity of co-regulatory proteins, constitutive activation of growth factor receptors, downregulation of proapoptotic signaling pathways, alteration in DNA response process and upregulation of prosurvival autophagy [6, 7]. By modulating such processes, tumor microenvironment has been suggested to contribute to anti-estrogen and chemotherapy resistance in breast and other types of cancer. Microenvironment conditions such as hypoxia and nutrient deprivation modulate prosurvival and pro-apoptotic signaling pathways by inducing stress and activating adaptive responses in tumor cells [8-10]. Hypoxia and nutrient deprivation in tumor microenvironment perturb the process of protein folding and induce stress in the endoplasmic reticulum (EnR) of cancer cells. Accumulation of unfolded proteins in the EnR sets off a series of adaptive mechanisms that together are known as unfolded protein response (UPR). UPR restores EnR homeostasis by
adjusting the protein folding capacity of the EnR and various other processes such as metabolism, energy production and cell differentiation [11]. UPR usually protects the cells from EnR stress, however, when severe or prolonged EnR stress cannot be mitigated, UPR eliminates stressed cells by apoptosis [12]. Activation of the UPR has been associated with therapy resistance and recurrence in breast cancer [10, 13]. The first evidence showing regulation of the EnR stress response by estrogen signaling in malignant breast was provided two decades ago [14]. The association of the two signaling pathways has been corroborated in several studies including those that have recently implicated both estrogen receptors in the regulation of the response [15, 16]. Estrogen impacts all three UPR pathways by regulating major transducers such as glucose regulated protein 78 (GRP78) and X-box binding protein-1 (XBP-1) that are upregulated in endocrine- and chemotherapy-resistant breast cancers [15, 17-24]. However, the impact of the hormone on UPR may vary in different breast cancer cell types depending on their context. In this review, we will provide insights into the mechanisms underlying the association of estrogen with the UPR signaling in breast cancer. We will also discuss how this crosstalk could lead to development of novel strategies to effectively regulate both signaling pathways and benefit patients with recurrent disease. Unfolded protein response EnR is the major compartment for folding of secretory and transmembrane proteins [25]. The process of protein folding is sensitive to alterations in rate of protein synthesis, glucose, oxygen and Ca2+ levels as well as redox imbalance and the presence of pathogens. These conditions lead to accumulation of unfolded proteins in the EnR lumen which is known as EnR stress. To cope with the EnR stress, cells activate the UPR which transiently decreases the rate of protein synthesis, increases the capacity of protein folding and reduces the overload of misfolded proteins through EnR-associated degradation (ERAD) and autophagy [11, 26-28]. In the
absence of misfolded proteins, the chaperone GRP78 binds to and prevents the activation of the EnR transmembrane proteins EnR-localized transmembrane protein inositol requiring enzyme 1 (IRE1), double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). Upon induction of EnR stress, GRP78 dissociates from its normal substrates to bind to unfolded proteins in the EnR lumen allowing the activation of the three UPR transducers [11]. Activation of PERK inhibits general protein synthesis through inactivation of the translation initiation factor eIF2α. Expression of the activating transcription factor ATF4 escapes the global translation block and promotes a gene expression program that regulates amino acid and redox metabolism, apoptosis and autophagy [11, 27, 29]. Activated IRE1 splices the mRNA that encodes the transcription factor XBP-1. This results in the expression of a strong transcription factor known as spliced XBP-1 (XBP-1s) that induces genes that promote protein folding and ERAD [30]. Another UPR pathway is initiated by the activation of ATF6. This occurs when ATF6 processing at Golgi produces a transcriptional activator that executes a pro-survival gene expression program [31, 32]. In addition to EnR, perturbation of the folding environment that leads to accumulation of misfolded proteins has been described in mitochondria [33]. Activation of mitochondrial UPR has been suggested to reduce proteotoxic stress in the organelle by upregulating nuclear genes that encode mitochondrial chaperones and proteases. Central role in the activation of this response in mammalian cells plays the transcription factor CHOP [34]. However, the precise mechanisms that sense the stress and activate the transducers of the mitochondrial UPR are poorly understood. Moreover, the relation of the response to cancer has not been established. While activation of the UPR in EnR restores physiological responses in various tissues, its aberrant activation has been detected in pathological conditions including metabolic disorder, inflammation, neurodegeneration, autoimmunity and cancer [11, 35]. Due to higher mitotic,
metabolic and in some tissues secretory activity, tumor cells require increased rate of protein synthesis that leads to alterations in protein folding and activation of the UPR. Similarly, UPR activation is observed in immune and endothelial cells of tumor stroma due to their increased synthesis and secretion of growth factors. In addition, cancer cells activate the UPR because they usually grow in hypoxic and hypoglycemic environment that disturbs protein folding [36]. Estrogen signaling and unfolded protein response in breast cancer Among the tissues with high secretory activity is the mammary gland. Estrogen regulates cell differentiation, proliferation and apoptosis that occur during lactation/involution cycles in normal mammary gland [37]. Estrogen signaling cooperates with the UPR to assist mammary cells to cope with the EnR stress that is induced during the synthesis and secretion of milk proteins [38]. The crosstalk between estrogen and UPR represents a dynamic signaling that is utilized by the neoplastic breast to adopt to stress in tumor microenvironment due to inadequate vascularization or the application of cytotoxic and endocrine therapies [10, 39, 40]. Endocrine is the standard therapy for patients with ERα-positive disease. However, intrinsic resistance to the anti-estrogen tamoxifen is seen in 50% of advanced ERα-positive tumors and as many as 40% of tamoxifen-treated cancers develop acquired resistance [10, 41]. Similar to ERα-positive disease, the majority of patients with TNBC tend not to respond to chemotherapy and develop resistant disease [42]. A growing body of evidence suggests that UPR regulates cell survival and apoptosis in breast tumors and determines their response to endocrine therapies and chemotherapies [10, 19, 23, 43]. Activation of the UPR in response to estrogenic stimulation was initially observed in the 90’s when 17β-estradiol was shown to protect ERα-positive breast cancer cells from thermal injury by inducing the expression of the heat shock protein 70 family member and UPR regulator GRP78 [14]. Several studies using cell-based and xenograft models have validated the UPR as one of the mechanisms employed by estrogen to regulate oncogenic responses in breast tumor
cells [15, 16, 38]. Estrogen induces the expression of the UPR components XBP-1 and GRP78 [23, 24, 44]. GRP78 and XBP-1 are overexpressed in 60-70% and 80-90% of breast tumors, respectively [3, 19, 22-24, 43, 45, 46]. Higher expression of XBP-1 mRNA was found in ERαpositive compared with the ERα-negative tumors suggesting that UPR is regulated by estrogen receptor [47]. This was further supported by the correlation of XBP-1 and GRP78 expression with that of ERα in breast tumors [23, 48]. High expression of XBP-1 and GRP78 was observed in anti-estrogen-resistant breast cancer cells in vitro [49] and endocrine-resistant breast tumors [2, 17, 18, 21, 50]. ERα and unfolded protein response in breast cancer Laboratory and clinically based studies have associated the UPR with ERα and endocrine therapy in breast cancer. XBP-1 was initially predicted as a key gene in an expression network that is associated with anti-estrogen resistance [51]. Correlation of XBP-1 with endocrine resistance was also observed in clinical breast cancer specimens during gene expression analysis [20, 48]. In addition to XBP-1, a UPR-associated gene expression signature has recently been identified as a powerful prognostic marker that predicts tamoxifen resistance in ERα-positive breast cancers. The same signature has also been associated with reduced time to recurrence and poor survival in the same breast cancer phenotype [15]. In addition to endocrine resistance, XBP-1 positivity was correlated with ERα expression in luminal breast cancers [2, 3]. More recently, by applying DNA microarray analysis several independent groups have identified XBP-1 as an estrogen responsive gene within the luminal cluster and an important feature of the gene expression signature that defines the luminal phenotype [52-54]. The clinical indication of XBP-1 as an estrogen responsive gene was corroborated in breast cancer cell-based studies. Estrogen-dependent regulation of XBP-1 expression was first observed by Finlin and colleagues and was subsequently validated by other groups [24, 44, 52, 53, 55]. Regions of the XBP-1 gene were identified among the ERα-regulated promoters
suggesting a potential regulation of XBP-1 transcription by estrogen and ERα [44]. Chromatin immunoprecipitation followed by microarray confirmed the recruitment of ERα on the promoter of XBP-1 gene [56]. More recently, Sengupta and colleagues have further corroborated the regulation of XBP-1 by estrogen and ERα and associated the upregulation of XBP-1 with estrogen-induced growth of ERα-positive breast cancer cells [24]. In addition to its identification as an estrogen responsive gene, XBP-1 was reported to regulate the expression and promote ligand-independent activation of ERα [56-59]. The transcriptional output of the ERα-XBP-1 cooperation may account for the decreased sensitivity of tumors that express both proteins to endocrine therapy [2, 3, 23, 50, 60, 61]. Indeed, coexpression of both unspliced and spliced forms of XBP-1 with full length-ERα correlates with enhanced ERα transcriptional activity in breast cancer cells. This is because ERα physically interacts with XBP-1 in a ligand-independent manner. The N-terminus of XBP-1 is indispensable for the interaction and essential for the effect of XBP-1 on ERα function [58]. The transcriptional complex involves another ERα co-activator, the steroid receptor co-activator 1 (SRC-1). SRC-1 cooperates with XBP-1 to promote large scale chromatin unfolding and increase the activity of the receptor [58, 59]. As a result, XBP-1s drives E2-independent activation of ERα and is more potent than the hormone in activating the receptor. In addition, XBP-1 potentiates the effects of estrogen on estrogen-dependent transcription in vitro [58]. The XBP-1-dependent activation of ERα enables estrogen-independent breast cancer cell growth. It also reduces the sensitivity of cells to the growth inhibitory effects of anti-estrogens both in vitro and in vivo [57]. Consistent with the cell growth effects, XBP-1s was found to regulate genes associated with apoptosis, cell cycle and estrogen responsiveness in ERα-positive breast cancer cells [57]. XBP-1s prevents cell cycle arrest and anti-estrogen-induced cell death by inhibiting the mitochondrial apoptotic pathway [57]. GRP78 is another estrogen-regulated UPR component that is overexpressed in human breast tumors [17, 23]. By upregulating pro-survival autophagy and inhibiting apoptosis, GRP78
contributes to endocrine resistance in ERα-positive breast cancers [17]. In response to EnR stress GRP78 activates all major UPR transducers and estrogen was found to upregulate all three arms of the UPR in ERα-positive breast cancer cells both in vitro and in vivo [15]. ERαdriven mild and transient UPR activation sustains cell survival and proliferation during EnR stress imposed by endocrine therapeutic interventions (Fig. 1). This may account for the decreased tamoxifen sensitivity of ERα-positive breast tumors that overexpress UPR-associated genes [15]. The prosurvival transient UPR activation in ERα-positive cells seems to be disrupted by the selective inhibition of ERα. In the presence of estrogen, BHPI, a potent noncompetitive ERα modulator has recently been found to promote a prolonged and pro-apoptotic UPR signaling that decreases the survival of endocrine-resistant breast cancer cells and induces tumor regression in a mouse model of breast cancer [15]. Thus, small molecules that inhibit ERα function and lead to irreversible activation of the UPR may represent novel therapeutics to overcome resistance in breast cancer [62]. Interestingly, similarly to EnR, ERα has been reported to mediate a cytoprotective UPR in mitochondria. Accumulation of unfolded proteins in mitochondria leads to estrogenindependent activation of ERα in breast cancer cells. In turn, activated ERα induces a gene expression program that increases the activity of proteasome to limit the accumulation of unfolded proteins and protect the integrity of the organelle [63]. Regulation of the unfolded protein response by ERβ While ERα promotes cell proliferation, anti-proliferative and anti-invasive responses have been observed following upregulation of wild-type ERβ in breast cancer cell lines [64-67]. Correlations between the expression of ERβ and clinical outcome have been explored in several studies. The majority of the studies examining patients with ERα-positive tumors have indicated that increased expression of wild-type ERβ (ERβ1) correlates with a more favorable response to endocrine therapy [68-70]. In patients with TNBC, ERβ1 expression has consistently been
associated with increased survival [70-72]. Several mechanisms to explain the tumor repressive actions of the receptor have been proposed. Among these, network modeling predicted a potential association of ERβ with the network topology of the UPR component [10]. However, the role of the receptor in the UPR signaling has not been experimentally studied until very recently when ERβ1 was reported to activate EnR stress-regulated cell death pathways [16]. In response to treatment with pharmacological EnR stress inducers, upregulation of ERβ1 or treatment with ligands that activate the receptor decreased the survival and enhanced apoptosis in both anti-estrogen sensitive and –resistant breast cancer cells. Upon EnR stress, ERβ1 downregulated the IRE1α and decreased the splicing and the activity of XBP-1 (Table 1). This effect was observed in ERα-positive and TN breast cancer cells suggesting the involvement of both ERα-dependent and -independent mechanisms. Given that XBP-1 drives progression in TNBC [19], the inhibitory effect of ERβ1 on UPR in TNBC cells may account for the previously described
association of
the
receptor
with
decreased
invasiveness
and
increased
chemosensitivity of TNBC cells [66, 73]. In addition, given that bortezomib is tested in clinical trials for treatment of metastatic breast cancer [74], the pro-apoptotic ERβ1 function in bortezomib-treated metastatic cells may suggest the combined use of ERβ agonists and bortezomib as an effective remedy for patients with metastatic disease. In contrast to wild-type isoform, the splice variant ERβ2 (also known as ERβcx) which differs from ERβ1 in 26 Cterminal amino acids did not alter XBP-1 activity and the sensitivity of breast cancer cells to EnR stress inducers [16]. The different effect of ERβ isoforms on UPR may account for their different associations with the clinical outcome in breast cancer patients [75]. Concluding remarks Activation of the UPR in breast cancer correlates with therapeutic resistance and worse clinical outcome. Targeting proximal UPR components that are often overexpressed in neoplastic breast has a great potential for breast cancer treatment. Several compounds have been
identified and are currently being tested in preclinical models and clinical settings [76]. Given that the UPR cooperates with other oncogenic factors to drive breast cancer progression, strategies that target more pathways seem to be more effective in combating resistant disease. Co-expression of XBP-1 and ERα in luminal phenotypes, the ligand-independent activation of ERα by XBP-1 and the activation of the cytoprotective UPR signaling by the receptor represent modes of UPR-estrogen signaling combined action that may drive estrogen independency and anti-estrogen resistance (Table 1). Thus, endocrine resistant tumors may benefit from a concomitant manipulation of the UPR and estrogen receptor activity. However, the ER subtypespecific expression changes in breast cancer and the distinct effects of ERs and their variants on UPR suggest selective targeting of estrogen signaling with ER subtype-specific ligands. The rationale of therapeutic strategies that intend to decrease protective UPR signaling responses through both UPR and ER subtype-selective targeting warrants further investigation. Future studies should clarify the specific effects of ER subtypes and their variant isoforms in various cytoprotective and pro-apoptotic UPR pathways as well as how different ER ligands affect the UPR responses.
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Figures Figure 1. Proposed mechanism illustrating the regulation of the UPR by estrogen receptors in breast cancer. Induction of EnR stress leads to activation of UPR transducers IRE1α, PERK and ATF6. PERK activation promotes cell survival by inhibiting global protein synthesis. Active IRE1α promotes splicing of XBP1 mRNA. This results in the generation of the transcription factor XBP-1s that induces the expression of cell survival genes. ERα upregulates all three arms of the UPR. ERα can promote cell survival by directly inducing the expression of XBP-1. In addition, XBP-1 binds to and activates ERα in the absence of estrogen. The interaction of ERα with XBP-1 leads to activation of a gene expression program that promotes endocrine resistance. In contrast, by downregulating IRE1α, ERβ1 decreases the expression of pro-survival XBP-1s and enhances EnR stress-regulated apoptosis.
Table 1. Effects of estrogen and estrogen receptors on UPR
ER ligands
Estrogen/ERα agonists activate the IRE1, PERK and ATF6 pathways
[14, 15, 17, 22-24, 44, 49, 52, 53, 55, 57]
ERβ agonists decrease XBP-1 activity
[16]
ERα activates the IRE1, PERK and ATF6 pathways
[15, 62]
Association between XBP-1 and endocrine resistance
[51]
XBP-1 is co-expressed with ERα in luminal tumors
[2, 3, 52-54]
High expression of XBP-1 in ERα-positive breast cancer
[2, 3, 18, 21, 23, 24, 44, 47,
XBP-1 interacts with ERα
[56-59]
GRP78 is overexpressed in ERα-positive breast cancers
[17, 18, 23]
Predicted association between XBP-1 and ERβ
[10]
ERβ1 downregulates the IRE1/XBP-1 pathway
[16]
ERα
ERβ
48, 50, 60, 61]