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Targeting GRP78 and antiestrogen resistance in breast cancer

    Katherine L Cook

    Department of Oncology & Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

    ,
    Pamela AG Clarke

    Department of Oncology & Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

    &
    Robert Clarke

    * Author for correspondence

    Department of Oncology & Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.

    Published Online:https://doi.org/10.4155/fmc.13.77

    Breast cancer is the most prevalent cancer in women, with over 200,000 new cases diagnosed each year. Over 70% of breast cancers express the estrogen receptor-α, and drugs targeting these receptors such as tamoxifen or Faslodex® often fail to cure these patients. Many estrogen receptor-positive tumors lose drug sensitivity, making endocrine resistance a major clinical problem. Recently, investigation into the molecular mechanisms of endocrine resistance has highlighted a causative role of the unfolded protein response in antiestrogen resistance. In particular, the master regulator of the unfolded protein response, GRP78, was observed to be elevated in endocrine-resistant breast cancer and directly affected antiestrogen therapy responsiveness. GRP78 was found to impact many different cellular processes that may affect breast cancer survival. Recently, various compounds have been reported to affect GRP78 activity and it may be advantageous to combine these drugs with antiestrogens to overcome endocrine therapy resistance.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Desantis C, Howlader N, Cronin KA, Jemal A. Breast cancer incidence rates in US women are no longer declining. Cancer Epidemiol. Biomarkers Prev.20(5),733–739 (2011).
    • Desantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J. Clin.61(6),409–418 (2011).
    • Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH. Pathways to tamoxifen resistance. Cancer Lett.256(1),1–24 (2007).
    • Riggins RB, Bouton AH, Liu MC, Clarke R. Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. Vitam. Horm.71,201–237 (2005).
    • Hong S, Didwania A, Olopade O, Ganschow P. The expanding use of third-generation aromatase inhibitors: what the general internist needs to know. J. Gen. Intern. Med.24(Suppl. 2),S383–S388 (2009).
    • Janicke F. Are all aromatase inhibitors the same? A review of the current evidence. Breast13(Suppl. 1),S10–S18 (2004).
    • Ingle JN, Suman VJ, Rowland KM et al. Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032. J. Clin. Oncol.24(7),1052–1056 (2006).
    • Perey L, Paridaens R, Hawle H et al. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of Phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann. Oncol.18(1),64–69 (2007).
    • Clarke R, Brunner N. Acquired estrogen independence and antiestrogen resistance in breast cancer: estrogen receptor driven phenotypes? Trends Endocrinol. Metab.7(8),291–301 (1996).
    • 10  Cook KL, Shajahan AN, Warri A, Jin L, Hilakivi-Clarke LA, Clarke R. Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res.72(13),3337–3349 (2012).▪▪ First report detailing role of GRP78 controling antiestrogen resistance.
    • 11  Clarke R, Skaar TC, Bouker KB et al. Molecular and pharmacological aspects of antiestrogen resistance. J. Steroid Biochem. Mol. Biol.76(1–5),71–84 (2001).
    • 12  Clarke R, Leonessa F, Welch JN, Skaar TC. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol. Rev.53(1),25–71 (2001).
    • 13  Bachleitner-Hofmann T, Pichler-Gebhard B, Rudas M et al. Pattern of hormone receptor status of secondary contralateral breast cancers in patients receiving adjuvant tamoxifen. Clin. Cancer Res.8(11),3427–3432 (2002).
    • 14  Clarke R, Liu MC, Bouker KB et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene22(47),7316–7339 (2003).
    • 15  Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. Biol. Chem.276(13),9817–9824 (2001).
    • 16  Gething MJ, Sambrook J. Protein folding in the cell. Nature355(6355),33–45 (1992).
    • 17  Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J.17(19),5708–5717 (1998).
    • 18  Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev.13(10),1211–1233 (1999).
    • 19  Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature397(6716),271–274 (1999).
    • 20  Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem.273(50),33741–33749 (1998).
    • 21  Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell107(7),881–891 (2001).
    • 22  Shen X, Ellis RE, Lee K et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell107(7),893–903 (2001).
    • 23  Harding HP, Zeng H, Zhang Y et al. Diabetes mellitus and exocrine pancreatic dysfunction in PERK-/- mice reveals a role for translational control in secretory cell survival. Mol. Cell7(6),1153–1163 (2001).
    • 24  Clarke R, Cook KL, Hu R et al. Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Cancer Res.72(6),1321–1331 (2012).▪▪ Review of the unfolded protein response, autophagy in estrogen receptor-positive breast cancer and endocrine resistance.
    • 25  Verfaillie T, Salazar M, Velasco G, Agostinis P. Linking ER stress to autophagy: potential implications for cancer therapy. Int. J. Cell Biol.2010,930509 (2010).
    • 26  Davies MP, Barraclough DL, Stewart C et al. Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer. Int. J. Cancer123(1),85–88 (2008).
    • 27  Fernandez PM, Tabbara SO, Jacobs LK et al. Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res. Treat.59(1),15–26 (2000).▪ Clinical data supporting role of GRP78 in breast tumors.
    • 28  Gazit G, Lu J, Lee AS. De-regulation of GRP stress protein expression in human breast cancer cell lines. Breast Cancer Res. Treat.54(2),135–146 (1999).
    • 29  Gomez BP, Riggins RB, Shajahan AN et al. Human X-box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines. FASEB J.21(14),4013–4027 (2007).
    • 30  Scriven P, Coulson S, Haines R, Balasubramanian S, Cross S, Wyld L. Activation and clinical significance of the unfolded protein response in breast cancer. Br. J. Cancer101(10),1692–1698 (2009).
    • 31  Gu Z, Lee RY, Skaar TC et al. Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780). Cancer Res.62(12),3428–3437 (2002).
    • 32  Fu Y, Li J, Lee AS. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res.67(8),3734–3740 (2007).▪ First report of implicating GRP78 in endocrine independence.
    • 33  Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J. Biol. Chem.278(23),20915–20924 (2003).
    • 34  Zhou H, Zhang Y, Fu Y, Chan L, Lee AS. Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J. Biol. Chem.286(29),25687–25696 (2011).
    • 35  Crawford AC, Riggins RB, Shajahan AN, Zwart A, Clarke R. Co-inhibition of BCL-W and BCL2 restores antiestrogen sensitivity through BECN1 and promotes an autophagy-associated necrosis. PLoS ONE5(1),e8604 (2010).
    • 36  He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Ann. Rev. Genet.43,67–93 (2009).
    • 37  Cook KL, Shajahan AN, Clarke R. Autophagy and endocrine resistance in breast cancer. Expert Rev. Anticancer Ther.11(8),1283–1294 (2011).
    • 38  Samaddar JS, Gaddy VT, Duplantier J et al. A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol. Cancer Ther.7(9),2977–2987 (2008).
    • 39  Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH, Barrett JT. Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy5(3),400–403 (2009).
    • 40  Clarke R, Shajahan AN, Riggins RB et al. Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. J. Steroid Biochem. Mol. Biol.114(1–2),8–20 (2009).
    • 41  Hoyer-Hansen M, Bastholm L, Szyniarowski P et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell25(2),193–205 (2007).
    • 42  Hoyer-Hansen M, Jaattela M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ.14(9),1576–1582 (2007).
    • 43  Li J, Ni M, Lee B, Barron E, Hinton DR, Lee AS. The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells. Cell Death Differ.15(9),1460–1471 (2008).
    • 44  Bennett HL, Fleming JT, O‘prey J, Ryan KM, Leung HY. Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells. Cell Death Dis.1,e72 (2010).
    • 45  Cook KL, Clarke R. Heat shock 70 kDa protein 5/glucose-regulated protein 78 ‘AMP‘ing up autophagy. Autophagy8(12),1827–1829 (2012).
    • 46  Hoyer-Hansen M, Jaattela M. AMP-activated protein kinase: a universal regulator of autophagy? Autophagy3(4),381–383 (2007).
    • 47  Grkovic S, O‘reilly VC, Han S, Hong M, Baxter RC, Firth SM. IGFBP-3 binds GRP78, stimulates autophagy and promotes the survival of breast cancer cells exposed to adverse microenvironments. Oncogene32(19),2412–2420 (2012).
    • 48  Li C, Harada A, Oh Y. IGFBP-3 sensitizes antiestrogen-resistant breast cancer cells through interaction with GRP78. Cancer Lett.325(2),200–206 (2012).
    • 49  Cook KL, Metheny-Barlow LJ, Tallant EA, Gallagher PE. Angiotensin-(1–7) reduces fibrosis in orthotopic breast tumors. Cancer Res.70(21),8319–8328 (2010).
    • 50  Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl Acad. Sci. USA108(7),2909–2914 (2011).
    • 51  Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure – an obstacle in cancer therapy. Nat. Rev. Cancer4(10),806–813 (2004).
    • 52  Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene29(34),4741–4751 (2010).
    • 53  Kalluri R. EMT. when epithelial cells decide to become mesenchymal-like cells. J. Clin. Invest.119(6),1417–1419 (2009).
    • 54  Zhou C, Nitschke AM, Xiong W et al. Proteomic analysis of tumor necrosis factor-alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype. Breast Cancer Res.10(6),R105 (2008).
    • 55  Hiscox S, Jiang WG, Obermeier K et al. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int. J. Cancer118(2),290–301 (2006).
    • 56  Li H, Song H, Luo J, Liang J, Zhao S, Su R. Knockdown of glucose-regulated protein 78 decreases the invasion, metalloproteinase expression and ECM degradation in hepatocellular carcinoma cells. J. Exp. Clin. Cancer Res.31,39 (2012).
    • 57  Su R, Li Z, Li H et al. GRP78 promotes the invasion of hepatocellular carcinoma. BMC Cancer10,20 (2010).
    • 58  Dong D, Ni M, Li J et al. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res.68(2),498–505 (2008).▪ First report of GRP78 promoting angiogenesis supporting the role of GRP78 in the tumor microenvironment.
    • 59  Dong D, Stapleton C, Luo B et al. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res.71(8),2848–2857 (2011).
    • 60  Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res.67(8),3496–3499 (2007).
    • 61  Nakagawa H, Yamamoto D, Kiyozuka Y et al. Effects of genistein and synergistic action in combination with eicosapentaenoic acid on the growth of breast cancer cell lines. J. Cancer Res. Clin. Oncol.126(8),448–454 (2000).
    • 62  Zhou Y, Lee AS. Mechanism for the suppression of the mammalian stress response by genistein, an anticancer phytoestrogen from soy. J. Natl Cancer Instit.90(5),381–388 (1998).
    • 63  Ermakova SP, Kang BS, Choi BY et al. (-)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res.66(18),9260–9269 (2006).
    • 64  Matsuo J, Tsukumo Y, Sakurai J et al. Preventing the unfolded protein response via aberrant activation of 4E-binding protein 1 by versipelostatin. Cancer Sci.100(2),327–333 (2009).
    • 65  Park HR, Chijiwa S, Furihata K, Hayakawa Y, Shin-Ya K. Relative and absolute configuration of versipelostatin, a down-regulator of molecular chaperone GRP78 expression. Org. Lett.9(8),1457–1460 (2007).
    • 66  Park HR, Tomida A, Sato S et al. Effect on tumor cells of blocking survival response to glucose deprivation. J. Natl Cancer Inst.96(17),1300–1310 (2004).
    • 67  Zhao P, Ueda JY, Kozone I et al. New glycosylated derivatives of versipelostatin, the GRP78/Bip molecular chaperone down-regulator, from Streptomyces versipellis 4083-SVS6. Org. Biomol. Chem.7(7),1454–1460 (2009).
    • 68  Umeda Y, Chijiwa S, Furihata K et al. Prunustatin A, a novel GRP78 molecular chaperone down-regulator isolated from Streptomyces violaceoniger. J. Antibiotic58(3),206–209 (2005).
    • 69  Umeda Y, Furihata K, Sakuda S et al. Absolute structure of prunustatin A, a novel GRP78 molecular chaperone down-regulator. Org. Lett.9(21),4239–4242 (2007).
    • 70  May KL, Paton JC, Paton AW. Escherichia coli subtilase cytotoxin induces apoptosis regulated by host Bcl-2 family proteins Bax/Bak. Infect. Immun.78(11),4691–4696 (2010).
    • 71  Paton AW, Beddoe T, Thorpe CM et al. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature443(7111),548–552 (2006).
    • 72  Paton AW, Paton JC. Escherichia coli subtilase cytotoxin. Toxins2(2),215–228 (2010).
    • 73  Ray R, De Ridder GG, Eu JP, Paton AW, Paton JC, Pizzo SV. The Escherichia coli subtilase cytotoxin A subunit specifically cleaves cell-surface GRP78 protein and abolishes COOH-terminal-dependent signaling. J. Biol. Chem.287(39),32755–32769 (2012).
    • 74  Dent P, Yacoub A, Grant S, Curiel DT, Fisher PB. MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J. Cell. Biochem.95(4),712–719 (2005).
    • 75  Gupta P, Walter MR, Su ZZ et al. BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. Cancer Res.66(16),8182–8191 (2006).
    • 76  Trondl R, Heffeter P, Jakupec M, Berger W, Keppler B. NKP-1339, a first-in-class anticancer drug showing mild side effects and activity in patients suffering from advanced refractory cancer. BMC Pharmacol. Toxicol.13(Suppl 1),A82 (2012).
    • 77  Groessl M, Hartinger CG. Anticancer metallodrug research analytically painting the ‘omics‘ picture-current developments and future trends. Anal. Bioanal. Chem.405(6),1791–1808 (2013).
    • 78  Yamazaki H, Hiramatsu N, Hayakawa K et al. Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. J. Immunol.183(2),1480–1487 (2009).
    • 79  Yahiro K, Morinaga N, Moss J, Noda M. Subtilase cytotoxin induces apoptosis in HeLa cells by mitochondrial permeabilization via activation of Bax/Bak, independent of C/EBF-homologue protein (CHOP), Ire1alpha or JNK signaling. Microb. Pathog.49(4),153–163 (2010).
    • 80  Yahiro K, Satoh M, Morinaga N et al. Identification of subtilase cytotoxin (SubAB) receptors whose signaling, in association with SubAB-induced BiP cleavage, is responsible for apoptosis in HeLa cells. Infect. Immun.79(2),617–627 (2011).
    • 81  Nakajima S, Hiramatsu N, Hayakawa K et al. Selective abrogation of BiP/GRP78 blunts activation of NF-kappaB through the ATF6 branch of the UPR. involvement of C/EBPbeta and mTOR-dependent dephosphorylation of Akt. Mol. Cell. Biol.31(8),1710–1718 (2011).
    • 82  Yahiro K, Morinaga N, Satoh M et al. Identification and characterization of receptors for vacuolating activity of subtilase cytotoxin. Mol. Microbiol.62(2),480–490 (2006).
    • 83  Arap MA, Lahdenranta J, Mintz PJ et al. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell6(3),275–284 (2004).
    • 84  Kim Y, Lillo AM, Steiniger SC et al. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry45(31),9434–9444 (2006).
    • 85  Schwarze S, Rangnekar VM. Targeting plasma membrane GRP78 for cancer growth inhibition. Cancer Biol. Ther.9(2),153–155 (2010).
    • 86  Rosenes Z, Mulhern TD, Hatters DM et al. The anti-cancer IgM monoclonal antibody PAT-SM6 binds with high avidity to the unfolded protein response regulator GRP78. PLoS ONE7(9),e44927 (2012).
    • 87  Cao Y, Chen A, An SS, Ji RW, Davidson D, Llinas M. Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth. J. Biol. Chem.272(36),22924–22928 (1997).
    • 88  Davidson DJ, Haskell C, Majest S et al. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. Cancer Res.65(11),4663–4672 (2005).
    • 89  Zhang D, Kaufman PL, Gao G, Saunders RA, Ma JX. Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats. Diabetologia44(6),757–765 (2001).
    • 90  Misra UK, Gonzalez-Gronow M, Gawdi G, Hart JP, Johnson CE, Pizzo SV. The role of GRP78 in alpha 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction. J. Biol. Chem.277(44),42082–42087 (2002).
    • 91  Mcfarland BC, Stewart J Jr, Hamza A et al. Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1. Cancer Res.69(13),5537–5545 (2009).
    • 92  Lee AS. The Par-4-GRP78 TRAIL, more twists and turns. Cancer Biol. Ther.8(22),2103–2105 (2009).
    • 93  Burikhanov R, Zhao Y, Goswami A, Qiu S, Schwarze SR, Rangnekar VM. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell138(2),377–388 (2009).
    • 94  Burikhanov R, Shrestha-Bhattarai T, Qiu S et al. Novel mechanism of apoptosis resistance in cancer mediated by extracellular Par-4. Cancer Res.73(2),1011–1019 (2013).
    • 101  Clinical trial indentification number: NCT01415297. http://clinicaltrials.gov/show/NCT01415297
    • 102  Clinical trial identification number: NCT01727778. www.clinicaltrials.gov/ct2/show/NCT01727778