Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is characterized as an aggressive form of breast cancer (BC) associated with poor patient outcomes. For the majority of patients, there is a lack of approved targeted therapies. Therefore, chemotherapy remains a key treatment option for these patients, but significant issues around acquired resistance limit its efficacy. Thus, TNBC has an unmet need for new targeted personalized medicine approaches. Calcium (Ca²⁺) is a ubiquitous second messenger that is known to control a range of key cellular processes by mediating signalling transduction and gene transcription. Changes in Ca²⁺ through altered calcium channel expression or activity are known to promote tumorigenesis and treatment resistance in a range of cancers including BC. Emerging evidence shows that this is mediated by Ca²⁺ modulation, supporting the function of tumour suppressor genes (TSGs) and oncogenes. This review provides insight into the underlying alterations in calcium signalling and how it plays a key role in promoting disease progression and therapy resistance in TNBC which harbours mutations in tumour protein p53 (TP53) and the PI3K/AKT pathway.

Keywords

Triple-negative breast cancer / TP53 / PI3K/AKT pathway / calcium

References

[1] Sung H,Siegel RL.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[2] Dawson S,Caldas C.Triple negative breast cancers: clinical and prognostic implications.EJC2009;45:27-40

[3] Dent R,Pritchard KI.Triple-negative breast cancer: clinical features and patterns of recurrence.Clin Cancer Res2007;13:4429-34

[4] Liedtke C,Hess KR.Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.J Clin Oncol2008;26:1275-81

[5] Lehmann BD,Chen X.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest2011;121:2750-67 PMCID:PMC3127435

[6] Lehmann BD,Chen X.Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection.PLoS One2016;11:e0157368 PMCID:PMC4911051

[7] Waks AG.Breast cancer treatment: a review.JAMA2019;321:288-300

[8] Burstein HJ.Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer.N Engl J Med2020;383:2557-70

[9] Elster N,Toomey S,Eustace AJ.HER2-family signalling mechanisms, clinical implications and targeting in breast cancer.Breast Cancer Res Treat2015;149:5-15

[10] Reddy KB.Triple-negative breast cancers: an updated review on treatment options.Curr Oncol2011;18:e173-9 PMCID:PMC3149549

[11] McCann KE,McAndrew N.Advances in targeted therapies for triple-negative breast cancer.Drugs2019;79:1217-30

[12] Lynce F.Role of platinums in triple-negative breast cancer.Curr Oncol Rep2021;23:50

[13] Litton JK,Ettl J.Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.N Engl J Med2018;379:753-63

[14] Tutt ANJ,Kaufman B.OlympiA clinical trial steering committee and investigatorsAdjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer.N Engl J Med2021;384:2394-405 PMCID:PMC9126186

[15] Lebert JM,Powell E,McCarthy J.Advances in the systemic treatment of triple-negative breast cancer.Curr Oncol2018;25:S142-50 PMCID:PMC6001760

[16] Schmid P,Rugo HS.IMpassion130 Trial InvestigatorsAtezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.N Engl J Med2018;379:2108-21

[17] Bardia A,Tolaney SM.ASCENT clinical trial investigatorsSacituzumab govitecan in metastatic triple-negative breast cancer.N Engl J Med2021;384:1529-41

[18] Monteith GR,Roberts-Thomson SJ.The calcium-cancer signalling nexus.Nat Rev Cancer2017;17:367-80

[19] Clapham DE.Calcium signaling.Cell2007;131:1047-58

[20] Stewart TA,Monteith GR.Altered calcium signaling in cancer cells.Biochim Biophys Acta2015;1848:2502-11

[21] Smedler E.Frequency decoding of calcium oscillations.Biochim Biophys Acta2014;1840:964-9

[22] Marchi S.Alterations of calcium homeostasis in cancer cells.Curr Opin Pharmacol2016;29:1-6

[23] Bittremieux M,Pinton P.ER functions of oncogenes and tumor suppressors: modulators of intracellular Ca²⁺ signaling.Biochim Biophys Acta2016;1863:1364-78

[24] So CL,Roberts-Thomson SJ.Calcium signalling and breast cancer.Semin Cell Dev Biol2019;94:74-83

[25] Monteith GR,Roberts-Thomson SJ.Calcium channels and pumps in cancer: changes and consequences.J Biol Chem2012;287:31666-73 PMCID:PMC3442501

[26] Raynal NJ,Wang Y.Targeting calcium signaling induces epigenetic reactivation of tumor suppressor genes in cancer.Cancer Res2016;76:1494-505 PMCID:PMC4794357

[27] Cui C,Fu L.Targeting calcium signaling in cancer therapy.Acta Pharm Sin B2017;7:3-17 PMCID:PMC5237760

[28] Bong AHL.Calcium signaling and the therapeutic targeting of cancer cells.Biochim Biophys Acta Mol Cell Res2018;1865:1786-94

[29] Catterall W. Calcium Channels. Encyclopedia of neuroscience. Elsevier; 2009. pp. 543-50.

[30] Bagur R.Intracellular Ca²⁺ sensing: its role in calcium homeostasis and signaling.Mol Cell2017;66:780-8 PMCID:PMC5657234

[31] Varghese E,Sadiq Z.Anti-cancer agents in proliferation and cell death: the calcium connection.IJMS2019;20:3017 PMCID:PMC6627763

[32] Foskett JK,Cheung KH.Inositol trisphosphate receptor Ca²⁺ release channels.Physiol Rev2007;87:593-658 PMCID:PMC2901638

[33] Berridge MJ.Inositol trisphosphate and diacylglycerol: two interacting second messengers.Annu Rev Biochem1987;56:159-93

[34] Endo M,Ogawa Y.Calcium induced release of calcium from the sarcoplasmic reticulum of skinned skeletal muscle fibres.Nature1970;228:34-6

[35] Liou J,Heo WD.STIM is a Ca²⁺ sensor essential for Ca²⁺-store-depletion-triggered Ca²⁺ influx.Curr Biol2005;15:1235-41 PMCID:PMC3186072

[36] Salido GM,Rosado JA.TRPC channels and store-operated Ca²⁺ entry.Biochim Biophys Acta2009;1793:223-30

[37] Worley PF,Huang GN.TRPC channels as STIM1-regulated store-operated channels.Cell Calcium2007;42:205-11 PMCID:PMC2764400

[38] Pla A, Kondratska K, Prevarskaya N. STIM and ORAI proteins: crucial roles in hallmarks of cancer.Am J Physiol Cell Physiol2016;310:C509-19

[39] Buchanan PJ.Ca_V channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics.Eur Biophys J2016;45:621-33 PMCID:PMC5045480

[40] Yang M.Membrane potential and cancer progression.Front Physiol2013;4 PMCID:PMC3713347

[41] O’Reilly D,Kouba S.CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer.Cell Calcium2022;103:102554

[42] Nielsen N,Schwab A.TRP channels and STIM/ORAI proteins: sensors and effectors of cancer and stroma cell migration.Br J Pharmacol2014;171:5524-40 PMCID:PMC4290700

[43] Tajada S.Calcium permeable channels in cancer hallmarks.Front Pharmacol2020;11:968 PMCID:PMC7358640

[44] Déliot N.Plasma membrane calcium channels in cancer: alterations and consequences for cell proliferation and migration.Biochim Biophys Acta2015;1848:2512-22

[45] Roderick HL.Ca²⁺ signalling checkpoints in cancer: remodelling Ca²⁺ for cancer cell proliferation and survival.Nat Rev Cancer2008;8:361-75

[46] Makena MR.Subtype specific targeting of calcium signaling in breast cancer.Cell Calcium2020;85:102109 PMCID:PMC6931135

[47] McAndrew D,Peters AA.ORAI1-mediated calcium influx in lactation and in breast cancer.Mol Cancer Ther2011;10:448-60

[48] Yang Y,Wang B.Expression of STIM1 is associated with tumor aggressiveness and poor prognosis in breast cancer.Pathol Res Pract2017;213:1043-7

[49] Motiani RK,Harmon KE.Orai3 is an estrogen receptor α-regulated Ca²⁺ channel that promotes tumorigenesis.FASEB J2013;27:63-75 PMCID:PMC3528310

[50] Chakraborty S,Banerjee B.Phemindole, a Synthetic Di-indole derivative maneuvers the store operated calcium entry (SOCE) to induce potent anti-carcinogenic activity in human triple negative breast cancer cells.Front Pharmacol2016;7:114 PMCID:PMC4854895

[51] Azimi I,Kaemmerer E.TRPC1 is a differential regulator of hypoxia-mediated events and Akt signalling in PTEN-deficient breast cancer cells.J Cell Sci2017;130:2292-305

[52] Lu C,Cheng X.Pathological role of ion channels and transporters in the development and progression of triple-negative breast cancer.Cancer Cell Int2020;20:377 PMCID:PMC7409684

[53] Lehmann BD,Silva TC.Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes.Nat Commun2021;12:6276 PMCID:PMC8560912

[54] Chen X,Gray WH.TNBCtype: A subtyping tool for triple-negative breast cancer.Cancer Inform2012;11:CIN.S9983 PMCID:PMC3412597

[55] Lehmann BD,Chen X.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest2011;121:2750-67

[56] Liu H,Karreth FA.Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple-negative breast cancer.Cancer Discov2018;8:354-69 PMCID:PMC5907916

[57] Duffy MJ,Crown J.Mutant p53 as a target for cancer treatment.Eur J Cancer2017;83:258-65

[58] Liu J,Feng Z.Tumor suppressor p53 and its gain-of-function mutants in cancer.Acta Biochim Biophys Sin (Shanghai)2014;46:170-9

[59] Coradini D,Ardoino I.p53 status identifies triple-negative breast cancer patients who do not respond to adjuvant chemotherapy.Breast2015;24:294-7

[60] Li JP,Zhang Z,Jindal S.Association of p53 expression with poor prognosis in patients with triple-negative breast invasive ductal carcinoma.Medicine (Baltimore)2019;98:e15449 PMCID:PMC6504250

[61] Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours.Nature2012;490:61-70 PMCID:PMC3465532

[62] Pan Y,Liu G.P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients.PLoS One2017;12:e0172324

[63] Biganzoli E,Ambrogi F.p53 status identifies two subgroups of triple-negative breast cancers with distinct biological features.Jpn J Clin Oncol2011;41:172-9

[64] Fournier MV,Chen J,Tannenbaum SH.A predictor of pathological complete response to neoadjuvant chemotherapy stratifies triple negative breast cancer patients with high risk of recurrence.Sci Rep2019;9:14863 PMCID:PMC6795899

[65] Dittmer D,Zambetti G.Gain of function mutations in p53.Nat Genet1993;4:42-6

[66] Yue X,Xu Y,Feng Z.Mutant p53 in cancer: accumulation, gain-of-function, and therapy.J Mol Biol2017;429:1595-606 PMCID:PMC5663274

[67] Baugh EH,Levine AJ,Chan CS.Why are there hotspot mutations in the TP53 gene in human cancers?.Cell Death Differ2018;25:154-60 PMCID:PMC5729536

[68] Klein K, Oualkacha K, Lafond MH, Bhatnagar S, Tonin PN, Greenwood CM. Gene coexpression analyses differentiate networks associated with diverse cancers harboring TP53 missense or null mutations.Front Genet2016;7:137 PMCID:PMC4971393

[69] Bittremieux M.p53 and Ca²⁺ signaling from the endoplasmic reticulum: partners in anti-cancer therapies.Oncoscience2015;2:233-8 PMCID:PMC4394128

[70] Haupt S,Haupt Y.p53 calls upon CIA (Calcium Induced Apoptosis) to counter stress.Front Oncol2015;5:57 PMCID:PMC4354267

[71] Bonora M.The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death.Front Oncol2014;4:302 PMCID:PMC4235083

[72] Giorgi C,Sorrentino G.p53 at the endoplasmic reticulum regulates apoptosis in a Ca²⁺-dependent manner.Proc Natl Acad Sci U S A2015;112:1779-84

[73] Nedeljković M.Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge.Cells2019;8:957 PMCID:PMC6770896

[74] Giorgi C,Missiroli S.Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling.Oncotarget2015;6:1435-45 PMCID:PMC4359305

[75] Rohacs T.Regulation of transient receptor potential channels by the phospholipase C pathway.Adv Biol Regul2013;53:341-55 PMCID:PMC3805701

[76] Nilius B,Voets T.Transient receptor potential cation channels in disease.Physiol Rev2007;87:165-217

[77] Gogna R,Keppler B.Gallium compound GaQ3-induced Ca²⁺ signalling triggers p53-dependent and -independent apoptosis in cancer cells: GaQ₃ induces Ca²⁺ signalling and p53 activation.Br J Pharmacol2012;166:617-36

[78] Madan E,Keppler B.p53 increases intra-cellular calcium release by transcriptional regulation of calcium channel TRPC6 in GaQ3-treated cancer cells.PLoS One2013;8:e71016 PMCID:PMC3745406

[79] Kischel P,Rodat-Despoix L.Ion channels: new actors playing in chemotherapeutic resistance.Cancers (Basel)2019;11:376 PMCID:PMC6468599

[80] Hasna J,Rodat-Despoix L.Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection.Cell Death Differ2018;25:693-707 PMCID:PMC5864197

[81] Brickley DR,Kopp RF.Serum- and glucocorticoid-induced protein kinase 1 (SGK1) is regulated by store-operated Ca²⁺ entry and mediates cytoprotection against necrotic cell death.J Biol Chem2013;288:32708-19 PMCID:PMC3820905

[82] Gibadulinova A,Pastorek J.Transcriptional regulation and functional implication of S100P in cancer.Amino Acids2011;41:885-92

[83] Cong Y,Wang S.Calcium-binding protein S100P promotes tumor progression but enhances chemosensitivity in breast cancer.Front Oncol2020;10:566302

[84] Arumugam T.S100P: a novel therapeutic target for cancer.Amino Acids2011;41:893-9 PMCID:PMC4041611

[85] Komatsu M,Matsuo T.Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis.Int J Oncol2013;42:478-506

[86] Maierthaler M,Peng C.S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer.Exp Mol Pathol2015;99:180-7

[87] Gibadulinova A,Filipcik P.Cancer-associated S100P protein binds and inactivates p53, permits therapy-induced senescence and supports chemoresistance.Oncotarget2016;7:22508-22 PMCID:PMC5008377

[88] Duffy MJ.Drugging “undruggable” genes for cancer treatment: are we making progress?.Int J Cancer2021;148:8-17

[89] Synnott NC,Crown J.COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells.Breast Cancer Res Treat2020;179:47-56

[90] Sallman DA,Garcia-Manero G.Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes.J Clin Oncol2021;39:1584-94 PMCID:PMC8099410

[91] Hemmings BA.PI3K-PKB/Akt pathway.Cold Spring Harb Perspect Biol2012;4:a011189 PMCID:PMC3428770

[92] Dong C,Chen Y,Chen C.Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer.Front Pharmacol2021;12:628690

[93] Costa RLB,Gradishar WJ.Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review.Breast Cancer Res Treat2018;169:397-406

[94] Pascual J.Targeting the PI3-kinase pathway in triple-negative breast cancer.Ann Oncol2019;30:1051-60

[95] Collavin L,Del Sal G.p53-family proteins and their regulators: hubs and spokes in tumor suppression.Cell Death Differ2010;17:901-11

[96] López-Knowles E,McNeil CM.PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality.Int J Cancer2010;126:1121-31

[97] Shah SP,Goya R.The clonal and mutational evolution spectrum of primary triple-negative breast cancers.Nature2012;486:395-9 PMCID:PMC3863681

[98] Pereira B,Rueda OM.The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.Nat Commun2016;7:11479 PMCID:PMC4866047

[99] Chen SMY,Nicklawsky AG.Deletion of p53 and hyper-activation of PIK3CA in Keratin-15⁺ stem cells lead to the development of spontaneous squamous cell carcinoma.Int J Mol Sci2020;21:6585 PMCID:PMC7554792

[100] Jiang YZ,Suo C.Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies.Cancer Cell2019;35:428-440.e5

[101] Chen L,Yao L.Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients.Nat Commun2018;9:1357 PMCID:PMC5893593

[102] Shi X,Lei Y,Tan D.Research progress on the PI3K/AKT signaling pathway in gynecological cancer (Review).Mol Med Rep2019;19:4529-35 PMCID:PMC6522820

[103] Porta C,Mosca A.Targeting PI3K/Akt/mTOR signaling in cancer.Front Oncol2014;4:64 PMCID:PMC3995050

[104] Showkat M,Andrabi KI.mTOR Signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions.Mol Biol Int2014;2014:686984 PMCID:PMC4258317

[105] Harms KL.The functional domains in p53 family proteins exhibit both common and distinct properties.Cell Death Differ2006;13:890-7

[106] Lee C,Waldman T.Activated PI3K signaling as an endogenous inducer of p53 in human cancer.Cell Cycle2007;6:394-6 PMCID:PMC4394610

[107] Singh B,Goberdhan A.p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas.Genes Dev2002;16:984-93 PMCID:PMC152354

[108] Astanehe A,Wasserman WW.Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer.J Cell Sci2008;121:664-74

[109] Wen J,Xiu HH,Xu KQ.Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in cancer: will they become a new battlefield for oncotherapy?.Chin J Cancer2016;35:32 PMCID:PMC4807559

[110] Marchi S,Bononi A.Selective modulation of subtype III IP₃R by Akt regulates ER Ca²⁺ release and apoptosis.Cell Death Dis2012;3:e304 PMCID:PMC3366079

[111] Marchi S,Giorgi C.Akt kinase reducing endoplasmic reticulum Ca²⁺ release protects cells from Ca²⁺-dependent apoptotic stimuli.Biochem Biophys Res Commun2008;375:501-5 PMCID:PMC2576286

[112] Milella M,Conciatori F.PTEN: multiple functions in human malignant tumors.Front Oncol2015;5:24 PMCID:PMC4329810

[113] Beg S,Prabhakaran S.Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.Breast Cancer Res Treat2015;151:541-53

[114] Li S,Wang M.Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis.Oncotarget2017;8:32043-54 PMCID:PMC5458267

[115] Bononi A,Marchi S.Identification of PTEN at the ER and MAMs and its regulation of Ca²⁺ signaling and apoptosis in a protein phosphatase-dependent manner.Cell Death Differ2013;20:1631-43 PMCID:PMC3824603

[116] Boehmerle W,Lazarus MB.Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism.Proc Natl Acad Sci U S A2006;103:18356-61 PMCID:PMC1838755

[117] Nguyen LD,Huynh LK.Characterization of NCS1-InsP3R1 interaction and its functional significance.J Biol Chem2019;294:18923-33 PMCID:PMC6901312

[118] Boehmerle W,Sivula M.Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation.Proc Natl Acad Sci U S A2007;104:11103-8 PMCID:PMC1904151

[119] Singh A,Tiwari S.Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics.J Cell Biochem2017;118:2333-46

[120] Leite MF,Echevarria W.Nuclear and cytosolic calcium are regulated independently.Proc Natl Acad Sci U S A2003;100:2975-80 PMCID:PMC151451

[121] Rodrigues MA,Leite MF.Nucleoplasmic calcium is required for cell proliferation.J Biol Chem2007;282:17061-8 PMCID:PMC2825877

[122] Guimarães E,Fonseca MC.Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer.PLoS One2017;12:e0175041 PMCID:PMC5380351

[123] Han F,Cai Z.The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance.Nat Commun2018;9:4728 PMCID:PMC6226490

[124] Jardin I,Salido GM.Store-operated Ca²⁺ entry in breast cancer cells: remodeling and functional role.Int J Mol Sci2018;19:4053

[125] Bhattacharya A,Hermanson K.The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression.Oncotarget2018;9:29468-83 PMCID:PMC6047677

[126] Davis FM,Faville RA.Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent.Oncogene2014;33:2307-16

[127] Zheng HC.The molecular mechanisms of chemoresistance in cancers.Oncotarget2017;8:59950-64 PMCID:PMC5601792

[128] Stewart TA,Thompson EW,Monteith GR.A role for calcium in the regulation of ATP-binding cassette, sub-family C, member 3 (ABCC3) gene expression in a model of epidermal growth factor-mediated breast cancer epithelial-mesenchymal transition.Biochem Biophys Res Commun2015;458:509-14

[129] Bong AHL,Roberts-Thomson SJ.Assessment of doxorubicin-induced remodeling of Ca²⁺ signaling and associated Ca²⁺ regulating proteins in MDA-MB-231 breast cancer cells.Biochem Biophys Res Commun2020;522:532-8

[130] Zhang P,Li H.TRPC5-induced autophagy promotes drug resistance in breast carcinoma via CaMKKβ/AMPKα/mTOR pathway.Sci Rep2017;7:3158 PMCID:PMC5466655

[131] Garrido-Castro AC,Barroso-Sousa R.Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.Breast Cancer Res2020;22:120 PMCID:PMC7607628

[132] Martín M,Dirix L.A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).Ann Oncol2017;28:313-20

[133] Schmid P,Chan S.Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.J Clin Oncol2020;38:423-33

[134] Turner N,O'Shaughnessy J.Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial.Breast Cancer Res Treat2022;191:565-76 PMCID:PMC8831286

[135] Liang X,Pan H,Han W.Development of store-operated calcium entry-targeted compounds in cancer.Front Pharmacol2021;12:688244 PMCID:PMC8194303

[136] Vashisht A,Motiani RK.STIM and Orai proteins as novel targets for cancer therapy. a review in the theme: cell and molecular processes in cancer metastasis.Am J Physiol Cell Physiol2015;309:C457-69 PMCID:PMC4593768

[137] Santos R,Gaulton A.A comprehensive map of molecular drug targets.Nat Rev Drug Discov2017;16:19-34 PMCID:PMC6314433

[138] Rahman S.Unveiling some FDA-approved drugs as inhibitors of the store-operated Ca²⁺ entry pathway.Sci Rep2017;7:12881 PMCID:PMC5643495

[139] Gutiérrez LG,Núñez L.Inhibition of polyamine biosynthesis reverses Ca²⁺ channel remodeling in colon cancer cells.Cancers (Basel)2019;11:83 PMCID:PMC6357118

[140] Zhang X,Liu X.Beyond a chemopreventive reagent, aspirin is a master regulator of the hallmarks of cancer.J Cancer Res Clin Oncol2019;145:1387-403

[141] Núñez L,Senovilla L,García-Sancho J.Cell proliferation depends on mitochondrial Ca²⁺ uptake: inhibition by salicylate.J Physiol2006;571:57-73 PMCID:PMC1805645

[142] Wang JY,Huang MY.STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.Oncogene2015;34:4358-67 PMCID:PMC4426254

[143] Li P,Chen GL.Mibefradil, a T-type Ca²⁺ channel blocker also blocks Orai channels by action at the extracellular surface.Br J Pharmacol2019;176:3845-56 PMCID:PMC6780027

[144] Im J.COX-2 regulates the insulin-like growth factor i-induced potentiation of Zn²⁺-toxicity in primary cortical culture.Mol Pharmacol2004;66:368-76

[145] Dobrydneva Y,Blackmore PF.Diethylstilbestrol and other nonsteroidal estrogens: novel class of store-operated calcium channel modulators.J Cardiovasc Pharmacol2010;55:522-30

[146] Tian C,Zhou Y.Store-operated CRAC channel inhibitors: opportunities and challenges.Future Med Chem2016;8:817-32 PMCID:PMC5558521

[147] Kang SS,Ku BM.Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.Cancer Res2010;70:1173-83 PMCID:PMC3273964

[148] Saleem H,Molinski TF.Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor.Br J Pharmacol2014;171:3298-312 PMCID:PMC4080982