Интеграция сигнальных каскадов фосфоинозитид-3-киназы (PI3K) и трансформирующего фактора роста β1 (TGF-β1): роль в реализации терапевтической неэффективности тамоксифена

Функционирование сигнальных каскадов факторов роста, их взаимодействие с центральными регуляторными мишенями опухолевых клеток и эстрогенами рассматриваются в качестве основных механизмов, опосредующих развитие гормональной резистентности при раке молочной железы. Результатом интеграции сигнального пути трансформирующего фактора роста β1 (TGF-β1) и PI3K (фосфоинозитид-3-киназа)/Akt (протеинкиназа B)/mTOR (мишень рапамицина млекопитающих) может являться активация пролиферативных процессов в клетках молочной железы и, как следствие, неэффективный ответ на терапию и прогрессирование заболевания. В обзоре представлен систематический анализ данных литературы, посвященной роли TGF-β1-сигнального пути в механизмах резистентности к тамоксифену в аспекте взаимодействия с каскадом PI3K/Akt/mTOR. Рассмотрены особенности взаимодействия сигнального пути рецепторов эстрогенов α, механизмы регуляторной активации TGF-β1 и PI3K/Akt/mTOR, а также их вклад в реализацию ответа на тамоксифен. Непосредственное вовлечение TGF-β1/PI3K в развитие устойчивости к данному препарату определяет перспективы изучения белков-эффекторов этих каскадов в качестве молекулярных мишеней. Накопленные к настоящему времени данные позволяют рассматривать сигнальный путь TGF-β1/PI3K как потенциальный молекулярный инструмент для поиска эффективных стратегий блокирования резистентности опухолевых клеток к тамоксифену.

1. Злокачественные новообразования в России в 2021 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: ФГБУ «МНИОИ им. П.А. Герцена» Минздрава России, 2022. 252 с.

2. Ferlay J., Colombet M., Soerjomataram I. et al. Cancer statistics for the year 2020. Int J Cancer 2021;10:778–89. DOI: 10.1002/ijc.33588

3. Burstein H.J., Curigliano G., Thürlimann B. et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol 2021;32(10):1216–35. DOI: 10.1016/j.annonc.2021.06.023

4. Jordan V.C. The role of tamoxifen in the treatment and prevention of breast cancer. Curr Probl Cancer 1992;16(3):129–76. DOI: 10.1016/0147-0272(92)90002-6

5. Zarzynska J.M. Two faces of TGF-beta1 in breast cancer. Mediators Inflamm 2014;2014:141747. DOI: 10.1155/2014/141747

6. Silberstein G.B., Daniel C.W. Reversible inhibition of mammary gland growth by transforming growth factor-beta. Science 1987;237(4812):291–3. DOI: 10.1126/science.3474783

7. Knabbe C., Lippman M.E., Wakefield L.M., et al. Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell 1987;48(3):417–28. DOI: 10.1016/0092-8674(87)90193-0

8. Lamouille S., Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007;178(3):437–51. DOI: 10.1083/jcb.200611146

9. Yoo Y.A., Kim Y.H., Kim J.S. et al. The functional implications of Akt activity and TGF-beta signaling in tamoxifen-resistant breast cancer. Biochim Biophys Acta 2008;1783(3):438–47. DOI: 10.1016/j.bbamcr.2007.12.001

10. Nardone A., De Angelis C., Trivedi M.V., et al. The changing role of ER in endocrine resistance. Breast 2015;242(2):60–6. DOI: 10.1016/j.breast.2015.07.015

11. Fuentes N., Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol 2019;116:135–70. DOI: 10.1016/bs.apcsb.2019.01.00

12. Dahlman-Wright K., Cavailles V., Fuqua S.A. et al. International union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006;58(4):773–81. DOI: 10.1124/pr.58.4.8

13. O’Lone R., Frith M.C., Karlsson E.K. et al. Genomic targets of nuclear estrogen receptors. Mol Endocrinol 2004;18(8):1859–75. DOI: 10.1210/me.2003-0044

14. Klinge C.M. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 2000;29(14):2905–19. DOI: 10.1093/nar/29.14.2905

15. Filardo E.J., Quinn J.A., Bland K.I. et al. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 2000;14(10):1649–60. DOI: 10.1210/mend.14.10.0532

16. Filardo E.J., Quinn J.A., Frackelton A.R. et al. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol Endocrinol 2002;16(1):70–84. DOI: 10.1210/mend.16.1.0758

17. Koszegi Z., Cheong R.Y. Targeting the non-classical estrogen pathway in neurodegenerative diseases and brain injury disorders. Front Endocrinol (Lausanne) 2022;13:999236. DOI: 10.3389/fendo.2022.999236

18. Prossnitz E.R., Barton M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol 2011;7(12):715–26. DOI: 10.1038/nrendo.2011.122

19. Ali S., Rasool M., Chaoudhry H. et al. Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation 2016;12(3):135–9. DOI: 10.6026/97320630012135

20. Hörlein A.J., Näär A.M., Heinzel T. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 1995;377(6548):397–404. DOI: 10.1038/377397a0

21. Heldring N., Pawson T., McDonnell D. et al. Structural insights into corepressor recognition by antagonist-bound estrogen receptors. J Biol Chem 2007;282(14):10449–55. DOI: 10.1074/jbc.M611424200

22. De Amicis F., Zupo S., Panno M.L. et al. Progesterone receptor B recruits a repressor complex to a half-PRE site of the estrogen receptor alpha gene promoter. Mol Endocrinol 2009;23(4):454–65. DOI: 10.1210/me.2008-0267

23. Bartella V., Rizza P., Barone I. et al. Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter. Breast Cancer Res Treat 2012;134(2):569–81. DOI: 10.1007/s10549-012-2090-9

24. Hurtado A., Holmes K.A., Geistlinger T.R. et al. Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature 2008;456(7222):663–6. DOI: 10.1038/nature07483

25. Syed V. TGF-β signaling in cancer. J Cell Biochem 2016;117(6):1279–87. DOI: 10.1038/nature07483

26. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990;6:597–641. DOI: 10.1146/annurev.cb.06.110190.003121

27. Gentry L.E., Lioubin M.N., Purchio A.F. et al. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol 1988;8(10):4162–8. DOI: 10.1128/mcb.8.10.4162–4168

28. Piek E., Heldin C.H., Ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 1999;13(15):2105–24.

29. Papageorgis P. TGFβ signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. J Oncol 2015;2015:587193. DOI: 10.1155/2015/587193

30. Lin H.Y., Wang X.F. Expression cloning of TGF-beta receptors. Mol Reprod Dev 1992;32(2):105–10. DOI: 10.1002/mrd.1080320205.

31. Massagué J. A very private TGF-beta receptor embrace. Mol Cell 2008;29(2):149–50. DOI: 10.1016/j.molcel.2008.01.006

32. Tzavlaki K., Moustakas A. TGF-β signaling. Biomolecules 2020;10(3):487. DOI: 10.3390/biom10030487

33. Denicourt C., Dowdy S.F. Another twist in the transforming growth factor beta-induced cell-cycle arrest chronicle. Proc Natl Acad Sci USA 2003;100(26):15290–301. DOI: 10.1073/pnas.0307282100

34. Babyshkina N., Malinovskaya E., Stakheyeva M. et al. Association of functional -509c>t polymorphism in the TGF-β1 gene with infiltrating ductal breast carcinoma risk in a Russian western Siberian population. Cancer Epidemiol 2011;35(6):560–63. DOI: 10.1016/j.canep.2011.02.002

35. Barcellos-Hoff M.H., Akhurst R.J. Transforming growth factor-beta in breast cancer: too much, too late. Breast Cancer Res 2009;11(1):202–7. DOI: 10.1186/bcr2224

36. Lee M.K., Pardoux C., Hall M.C. et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 2007;26(17):3957–67. DOI: 10.1038/sj.emboj.7601818

37. McKay M.M., Morrison D.K. Integrating signals from RTKs to ERK/MAPK. Oncogene 2007;26(22):3113–22. DOI: 10.1038/sj.onc.1210394

38. van der Geer P., Hunter T., Lindberg R.A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994;10:251–337. DOI: 10.1146/annurev.cb.10.110194.001343

39. Zhang Y.E. Non-Smad pathways in TGF-beta signaling. Cell Res 2009;19(1):128–39. DOI: 10.1038/cr.2008.328

40. Kim S., Kim S.A., Han J., et al. Rho-Kinase as a target for cancer therapy and its immunotherapeutic potential. Int J Mol Sci 2021;22(23):12916–36. DOI: 10.3390/ijms222312916

41. Sahai E., Marshall C.J. RHO-GTPases and cancer. Nat Rev Cancer 2002;2(2):133–42. DOI: 10.1038/nrc725

42. Panková K., Rösel D., Novotný M. et al. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol Life Sci 2010;67(1):63–71. DOI: 10.1007/s00018-009-0132-1

43. Taddei M.L., Giannoni E., Morandi A. et al. Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells. Cell Commun Signal 2014;12:24–35. DOI: 10.1186/1478-811X-12-24

44. Yamashita M., Fatyol K., Jin C. et al. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 2008;31(6):918–24. DOI: 10.1016/j.molcel.2008.09.002

45. Paplomata E., O’Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol 2014;6(4):154–66. DOI: 10.1177/1758834014530023

46. Backer J.M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 2008;410(1):1–17. DOI: 10.1042/BJ20071427

47. Vadas O., Burke J.E., Zhang X. et al. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci Signal 2011;4(195):re2. DOI: 10.1126/scisignal.2002165

48. Brown J.R., Auger K.R. Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery. BMC Evol Biol 2011;11:4–17. DOI: 10.1186/1471-2148-11-4

49. Yu X., Long Y.C., Shen H.M. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy 2015;11(10):1711–28. DOI: 10.1080/15548627.2015.1043076

50. Falasca M., Hughes W.E., Dominguez V. et al. The role of phosphoinositide 3-kinase C2alpha in insulin signaling. J Biol Chem 2007;282(38):28226–36. DOI: 10.1074/jbc.M704357200

51. Braccini L., Ciraolo E., Campa C.C. et al. PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat Commun 2015;6:7400–15. DOI: 10.1038/ncomms8400

52. Backer J.M. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem J 2016;473(15): 2251–71. PMID: 35295334. DOI: 10.3389/fphar.2022.791272

53. Hinz N., Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Commun Signal 2019;17(1):154–82. DOI: 10.1186/s12964-019-0450-3

54. Kim C.Y., Kim Y.C., Oh J.H. et al. HOXA5 confers tamoxifen resistance via the PI3K/AKT signaling pathway in ER-positive breast cancer. J Cancer 2021;12(15):4626–37. DOI: 10.7150/jca.59740

55. Hamadneh L., Bahader M., Abuarqoub R. et al. PI3K/AKT and MAPK1 molecular changes preceding matrix metallopeptidases overexpression during tamoxifen-resistance development are correlated to poor prognosis in breast cancer patients. Breast Cancer 2021;28(6):1358–66. DOI: 10.1007/s12282-021-01277-2

56. Tanic N., Milovanovic Z., Tanic N. et al. The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biol Ther 2012;13(12):1165–74. DOI: 10.4161/cbt.21346

57. Hamadneh L., Abuarqoub R., Alhusban A. et al. Upregulation of PI3K/AKT/PTEN pathway is correlated with glucose and glutamine metabolic dysfunction during tamoxifen resistance development in MCF-7 cells. Sci Rep 2020;10:21933–40. DOI: 10.1038/s41598-020-78833-x

58. Baba A.B., Rah B., Bhat G.R. et al. Transforming growth factor-beta (TGF-β) signaling in cancer-A betrayal within. Front Pharmacol 2022;13:791272–87. DOI: 10.3389/fphar.2022.791272

59. Bakin A.V., Tomlinson A.K., Bhowmick N.A. et al. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000;275(47):36803–10. DOI: 10.1074/jbc.M005912200

60. Jechlinger M., Sommer A., Moriggl R. et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 2006;116(6):1561–70. DOI: 10.1172/JCI24652

61. Yi J.Y., Shin I., Arteaga C.L. Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem 2005;280(11):10870–76. DOI: 10.1074/jbc.M413223200

62. Viñals F., Pouysségur J. Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Mol Сell Вiol 2001;21(21):7218–30. DOI: 10.1128/MCB.21.21.7218-7230.2001

63. Valderrama-Carvajal H., Cocolakis E., Lacerte A. et al. Activin/ TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nat Cell Biol 2002;4(12):963–9. DOI: 10.1038/ncb885

64. Conery A.R., Cao Y., Thompson E.A. et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6(4):366–72. DOI: 10.1038/ncb1117

65. Perry R.R., KangY., Greaves B.R. Relationship between tamoxifen induced transforming growth factor beta 1 expression, cytostasis and apoptosis in human breast cancer cells. Br J Cancer 1995;72(6):1441–6. DOI: 10.1038/bjc.1995.527

66. Fry M.J. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res 2001;3(5):304–12. DOI: 10.1186/bcr312

67. Jordan N.J., Gee J.M., Barrow D. et al. Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells. Breast Cancer Res Treat 2004;87(2):167–80. DOI: 10.1023/B:BREA.0000041623.21338.47

68. Дронова Т.А., Бабышкина Н.Н., Завьялова М.В. и др. Взаимосвязь компонентов EGFR/PI3K/Akt-сигнального пути с эффективностью терапии тамоксифеном у больных эстрогензависимым раком молочной железы. Успехи молекулярной онкологии 2018;5(3):40–50. DOI: 17650/2313-805X-2018-5-3-40-50

69. Frogne T., Jepsen J.S., Larsen S.S. et al. Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth. Endocr Relat Cancer 2005;12(3):599–614. DOI: 10.1677/erc.1.00946

70. Beeram M., Tan Q.T., Tekmal R.R. et al. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 2007;18(8):1323–8. DOI: 10.1093/annonc/mdm170

71. Дронова Т.А., Бабышкина Н.Н., Слонимская Е.М. и др. Рецептор трансформирующего фактора роста II типа (TGFβR2) и pAKT: связь с формированием резистентного к гормонотерапии фенотипа эстроген-позитивных опухолей молочной железы. В кн.: VII Петербургский международный онкологический форум «Белые ночи 2021». Материалы VII Петербургского международного онкологического форума. Санкт-Петербург, 2021. С. 255.

72. Fan M., Yan P.S., Hartman-Frey C. et al. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res 2006;66(24):11954–66. DOI: 10.1158/0008-5472

73. Radiation therapy and M7824 in treating patients with metastatic hormone receptor positive, HER2 negative breast cancer. Available at: https://clinicaltrials.gov/study/NCT03524170.

74. Formenti S.C., Lee P., Adams S. et al. Focal irradiation and systemic TGFβ blockade in metastatic breast cancer. Clin Cancer Res 2018;24(11):2493–2504. DOI: 10.1158/1078-0432.CCR-17-3322

75. Jung S.Y., Yug J.S., Clarke J.M. et al. Population pharmacokinetics of vactosertib, a new TGF-β receptor type Ι inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol 2020;85(1):173–83. DOI: 10.1007/s00280-019-03979-z

76. Baselga J., Im S.A., Iwata H. et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18(7):904–16. DOI: 10.1016/S1470-2045(17)30376-5

77. Di Leo A., Johnston S., Lee K.S. et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018;19(1):87–100. DOI: 10.1016/S1470-2045(17)30688-5

78. Krop I.E., Mayer I.A., Ganju V. et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2016;17(6):811–21. DOI: 10.1016/S1470-2045(16)00106-6

79. Baselga J., Dent S.F. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. J Clin Oncol 2018:36(Suppl. 18):LBA1006. DOI: 10.1200/JCO.2018.36.18_suppl.LBA1006

80. Markham A. Alpelisib: first global approval. Drugs 2019;79(11):1249–53. DOI: 10.1007/s40265-019-01161-6

81. André F., Ciruelos E., Rubovszky G. et al. SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380(20):1929–40. DOI: 10.1056/NEJMoa1813904

82. Lu Y.S., Lee K.S., Chao T.Y. et al. A Phase Ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with HR-positive HER2-negative advanced breast cancer. Clin Cancer Res 2021;27(2):408–17. DOI: 10.1158/1078-0432.CCR-20-1008

83. ClinicalTrials.gov. to evaluate the safety, tolerability, and pharmacokinetics of inavolisib single agent in participants with solid tumors and in combination with endocrine and targeted therapies in participants with breast cancer. Available at: https://clinicaltrials.gov/study/NCT03006172

84. Jones R.H., Casbard A., Carucci M. et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2020;21(3):345–57. DOI: 10.1016/S1470-2045(19)30817-4

85. Ma C.X., Suman V., Goetz M.P. et al. A Phase II trial of neoadjuvant MK-2206, an AKT Inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer. Clin Cancer Res 2017;23(22):6823–32. DOI: 10.1158/1078-0432.CCR-17-1260