Combination treatment with proteasome inhibitors and antiestrogens has a synergistic effect mediated by p21WAF1 in estrogen receptor-positive breast cancer

Maynadier,Marie; Basile,Ilaria; Gallud,Audrey; Gary-Bobo,Magali; Garcia,Marcel

doi:10.3892/or.2016.4873

Combination treatment with proteasome inhibitors and antiestrogens has a synergistic effect mediated by p21WAF1 in estrogen receptor-positive breast cancer

Authors:
- Marie Maynadier
- Ilaria Basile
- Audrey Gallud
- Magali Gary-Bobo
- Marcel Garcia
View Affiliations

Affiliations: Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université Montpellier, ENSCM, Faculté de Montpellier, 34093 Montpellier Cedex 5, France
Published online on: June 14, 2016 https://doi.org/10.3892/or.2016.4873
Pages: 1127-1134

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Although antiestrogens significantly improve the survival of patients with ER-positive breast cancer, therapeutic resistance remains a major limitation. The combinatorial use of antiestrogen with other therapies was proposed to increase their efficiency and more importantly, to prevent or delay the resistance phenomenon. In the present study, we addressed their combined effects with proteasome inhibitors (PIs). The effects of antiestrogens (hydroxyl-tamoxifen, raloxifen and fulvestrant) currently used in endocrine therapy were tested in combination with PIs, bortezomib or MG132, on the growth of three ER-positive breast cancer cell lines and in two cellular models of acquired antiestrogen resistance. When compared to single treatments, these combined treatments were significantly more effective in preventing the growth of the cell lines. The regulation of key cell cycle proteins, the cyclin-dependent kinase inhibitors, p21WAF1 and p27KIP1, were also studied. Bortezomib and MG132 drastically increased p21WAF1 expression through elevation of its mRNA concentration. Notably, p27KIP1 regulation was quite different from that of p21WAF1. Furthermore, the effect of bortezomib in combination with antiestrogen was evaluated on antiestrogen-resistant cell lines. The growth of two antiestrogen-resistant cell lines appeared responsive to proteasome inhibition and was strongly decreased by a combined therapy with an antiestrogen. Collectively, these findings provide new perspectives for the use of PIs in combination with endocrine therapies for breast cancer and possibly to overcome acquired hormonal resistance.

View Figures

View References

1	Henderson BE, Ross R and Bernstein L: Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation award lecture. Cancer Res. 48:246–253. 1988.PubMed/NCBI
2	Couse JF and Korach KS: Estrogen receptor null mice: What have we learned and where will they lead us? Endocr Rev. 20:358–417. 1999. View Article : Google Scholar : PubMed/NCBI
3	McDonnell DP, Connor CE, Wijayaratne A, Chang CY and Norris JD: Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators. Recent Prog Horm Res. 57:295–316. 2002. View Article : Google Scholar : PubMed/NCBI
4	Ikeda H, Taira N, Nogami T, Shien K, Okada M, Shien T, Doihara H and Miyoshi S: Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. Cancer Sci. 102:2038–2042. 2011. View Article : Google Scholar : PubMed/NCBI
5	Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N and Slingerland JM: Down-regulation of p21^WAF1/CIP1 or p27^Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc Natl Acad Sci USA. 97:9042–9046. 2000. View Article : Google Scholar
6	Maynadier M, Ramirez JM, Cathiard AM, Platet N, Gras D, Gleizes M, Sheikh MS, Nirde P and Garcia M: Unliganded estrogen receptor alpha inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21^WAF1). FASEB J. 22:671–681. 2008. View Article : Google Scholar
7	Planas-Silva MD and Weinberg RA: Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol. 17:4059–4069. 1997. View Article : Google Scholar : PubMed/NCBI
8	Varshochi R, Halim F, Sunters A, Alao JP, Madureira PA, Hart SM, Ali S, Vigushin DM, Coombes RC and Lam EW: ICI182,780 induces p21^WAF1 gene transcription through releasing histone deacetylase 1 and estrogen receptor alpha from Sp1 sites to induce cell cycle arrest in MCF-7 breast cancer cell line. J Biol Chem. 280:3185–3196. 2005. View Article : Google Scholar
9	Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, et al: Decreased levels of the cell-cycle inhibitor p27^Kip1 protein: Prognostic implications in primary breast cancer. Nat Med. 3:227–230. 1997. View Article : Google Scholar : PubMed/NCBI
10	Tan P, Cady B, Wanner M, Worland P, Cukor B, Magi-Galluzzi C, Lavin P, Draetta G, Pagano M and Loda M: The cell cycle inhibitor p27 is an independent prognostic marker in small (T_1a,b) invasive breast carcinomas. Cancer Res. 57:1259–1263. 1997.PubMed/NCBI
11	Wakasugi E, Kobayashi T, Tamaki Y, Ito Y, Miyashiro I, Komoike Y, Takeda T, Shin E, Takatsuka Y, Kikkawa N, et al: p21(Waf1/Cip1) and p53 protein expression in breast cancer. Am J Clin Pathol. 107:684–691. 1997. View Article : Google Scholar : PubMed/NCBI
12	Tiezzi DG, Andrade JM, Ribeiro-Silva A, Zola FE, Marana HR and Tiezzi MG: HER-2, p53, p21 and hormonal receptors proteins expression as predictive factors of response and prognosis in locally advanced breast cancer treated with neoadjuvant docetaxel plus epirubicin combination. BMC Cancer. 7:362007. View Article : Google Scholar : PubMed/NCBI
13	Sáez A, Sánchez E, Sánchez-Beato M, Cruz MA, Chacón I, Muñoz E, Camacho FI, Martínez-Montero JC, Mollejo M, García JF, et al: p27^Kip1 is abnormally expressed in diffuse large B-cell lymphomas and is associated with an adverse clinical outcome. Br J Cancer. 80:1427–1434. 1999. View Article : Google Scholar
14	Tsihlias J, Kapusta L and Slingerland J: The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 50:401–423. 1999. View Article : Google Scholar : PubMed/NCBI
15	Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S and Elliott PJ: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res. 59:2615–2622. 1999.PubMed/NCBI
16	Uddin S, Ahmed M, Bavi P, El-Sayed R, Al-Sanea N, AbdulJabbar A, Ashari LH, Alhomoud S, Al-Dayel F, Hussain AR, et al: Bortezomib (Velcade) induces p27^Kip1 expression through S-phase kinase protein 2 degradation in colorectal cancer. Cancer Res. 68:3379–3388. 2008. View Article : Google Scholar : PubMed/NCBI
17	Dulić V, Stein GH, Far DF and Reed SI: Nuclear accumulation of p21^Cip1 at the onset of mitosis: A role at the G₂/M-phase transition. Mol Cell Biol. 18:546–557. 1998. View Article : Google Scholar
18	Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J and Anderson KC: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61:3071–3076. 2001.PubMed/NCBI
19	Ludwig H, Khayat D, Giaccone G and Facon T: Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer. 104:1794–1807. 2005. View Article : Google Scholar : PubMed/NCBI
20	Chen F and Harrison LE: Ciglitazone-induced cellular anti-proliferation increases p27^Kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation. Cell Signal. 17:809–816. 2005. View Article : Google Scholar : PubMed/NCBI
21	Maynadier M, Shi J, Vaillant O, Gary-Bobo M, Basile I, Gleizes M, Cathiard AM, Wah JL, Sheikh MS and Garcia M: Roles of estrogen receptor and p21^Waf1 in bortezomib-induced growth inhibition in human breast cancer cells. Mol Cancer Res. 10:1473–1481. 2012. View Article : Google Scholar : PubMed/NCBI
22	Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 348:2609–2617. 2003. View Article : Google Scholar : PubMed/NCBI
23	Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 20:4420–4427. 2002. View Article : Google Scholar : PubMed/NCBI
24	Powers GL, Ellison-Zelski SJ, Casa AJ, Lee AV and Alarid ET: Proteasome inhibition represses ERalpha gene expression in ER⁺ cells: A new link between proteasome activity and estrogen signaling in breast cancer. Oncogene. 29:1509–1518. 2010. View Article : Google Scholar
25	Brünner N, Frandsen TL, Holst-Hansen C, Bei M, Thompson EW, Wakeling AE, Lippman ME and Clarke R: MCF7/LCC2: A 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. Cancer Res. 53:3229–3232. 1993.PubMed/NCBI
26	Faye JC, Jozan S, Redeuilh G, Baulieu EE and Bayard F: Physicochemical and genetic evidence for specific antiestrogen binding sites. Proc Natl Acad Sci USA. 80:3158–3162. 1983. View Article : Google Scholar : PubMed/NCBI
27	Gary-Bobo M, Hocine O, Brevet D, Maynadier M, Raehm L, Richeter S, Charasson V, Loock B, Morère A, Maillard P, et al: Cancer therapy improvement with mesoporous silica nanoparticles combining targeting, drug delivery and PDT. Int J Pharm. 423:509–515. 2012. View Article : Google Scholar
28	Prud'homme GJ, Glinka Y, Toulina A, Ace O, Subramaniam V and Jothy S: Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PloS One. 5:e138312010. View Article : Google Scholar : PubMed/NCBI
29	Maynadier M, Chambon M, Basile I, Gleizes M, Nirde P, Gary-Bobo M and Garcia M: Estrogens promote cell-cell adhesion of normal and malignant mammary cells through increased desmosome formation. Mol Cell Endocrinol. 364:126–133. 2012. View Article : Google Scholar : PubMed/NCBI
30	Pérez-Tenorio G, Berglund F, Esguerra Merca A, Nordenskjöld B, Rutqvist LE, Skoog L and Stål O: Cytoplasmic p21^WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer. Int J Oncol. 28:1031–1042. 2006.
31	Shah MH, Young D, Kindler HL, Webb I, Kleiber B, Wright J and Grever M: Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res. 10:6111–6118. 2004. View Article : Google Scholar : PubMed/NCBI
32	Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, Pien CS, Millikan RE, Tu SM, Pagliaro L, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 22:2108–2121. 2004. View Article : Google Scholar : PubMed/NCBI
33	Blaney SM, Bernstein M, Neville K, Ginsberg J, Kitchen B, Horton T, Berg SL, Krailo M and Adamson PC: Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: A Children's Oncology Group study (ADVL0015). J Clin Oncol. 22:4804–4809. 2004. View Article : Google Scholar : PubMed/NCBI
34	Awada A, Albanell J, Canney PA, Dirix LY, Gil T, Cardoso F, Gascon P, Piccart MJ and Baselga J: Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: A phase I/II dose-escalation study. Br J Cancer. 98:1500–1507. 2008. View Article : Google Scholar : PubMed/NCBI
35	Kim JE, Yoon DH, Jang G, Lee DH, Kim S, Park CS, Huh J, Kim WS, Park J, Lee JH, et al: A phase I/II study of bortezomib plus CHOP every 2 weeks (CHOP-14) in patients with advanced-stage diffuse large B-cell lymphomas. Korean J Hematol. 47:53–59. 2012. View Article : Google Scholar : PubMed/NCBI
36	Houot R, Le Gouill S, Ojeda Uribe M, Mounier C, Courby S, Dartigeas C, Bouabdallah K, Alexis Vigier M, Moles MP, Tournilhac O, et al French GOELAMS group: Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: Results of a phase II trial from the GOELAMS. Ann Oncol. 23:1555–1561. 2012. View Article : Google Scholar
37	Periyasamy-Thandavan S, Jackson WH, Samaddar JS, Erickson B, Barrett JR, Raney L, Gopal E, Ganapathy V, Hill WD, Bhalla KN, et al: Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER⁺ breast cancer cells. Autophagy. 6:19–35. 2010. View Article : Google Scholar : PubMed/NCBI
38	Lu Z and Hunter T: Ubiquitylation and proteasomal degradation of the p21^Cip1, p27^Kip1 and p57^Kip2 CDK inhibitors. Cell Cycle. 9:2342–2352. 2010. View Article : Google Scholar : PubMed/NCBI
39	Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S and Benz CC: Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer. 7:592007. View Article : Google Scholar : PubMed/NCBI
40	O'Regan RM, Osipo C, Ariazi E, Lee ES, Meeke K, Morris C, Bertucci A, Sarker MA, Grigg R and Jordan VC: Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice. Clin Cancer Res. 12:2255–2263. 2006. View Article : Google Scholar : PubMed/NCBI
41	Fox EM, Arteaga CL and Miller TW: Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer. Front Oncol. 2:1452012. View Article : Google Scholar
42	Shaw LE, Sadler AJ, Pugazhendhi D and Darbre PD: Changes in oestrogen receptor-alpha and -beta during progression to acquired resistance to tamoxifen and fulvestrant (Faslodex, ICI 182,780) in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol. 99:19–32. 2006. View Article : Google Scholar : PubMed/NCBI