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HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer

Oncogene volume 40, pages 5314–5326 (2021)Cite this article

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Abstract

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells. HDACi slowed breast cancer cell proliferation and reduced primary tumor growth. Primary breast tumors from HDACi-treated patients had increased LIFR levels and reduced proliferation rates compared to pre-treatment levels. Recent Phase II clinical trial data studying entinostat and azacitidine in metastatic breast cancer revealed that induction of several pro-dormancy genes post-treatment was associated with prolonged patient survival. Together, these findings suggest HDACi as a potential therapeutic avenue to promote dormancy, prevent recurrence, and improve patient outcomes in breast cancer.

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Fig. 1: HDAC inhibitors induce LIFR mRNA and protein expression in breast cancer cells.
Fig. 2: Epigenetic regulation of LIFR by HDAC inhibitors and activation of downstream STAT3 signaling.
Fig. 3: HDACi stimulate a pro-dormancy gene program.
Fig. 4: HDACi-stimulated pro-dormancy phenotype results in slowed tumor cell proliferation and reduced primary tumor growth.
Fig. 5: HDACi-induced dormancy phenotype is inversely associated with proliferation and recurrence in breast cancer patients.
Fig. 6: Induction of pro-dormancy genes following entinostat and azacitidine treatment is associated with longer breast cancer patient survival.

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References

  1. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008;13:58–68.

    Article  PubMed  CAS  Google Scholar 

  2. Hosseini H, Obradovic MM, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540:552–8.

  3. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7:834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gomis RR, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11:62–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Sanger N, Effenberger KE, Riethdorf S, Van Haasteren V, Gauwerky J, Wiegratz I, et al. Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int J Cancer. 2011;129:2522–6.

    Article  PubMed  CAS  Google Scholar 

  6. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13:673–91.

    Article  CAS  PubMed  Google Scholar 

  7. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92–92.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci, 2017;18:1414.

  10. Chen D, Sun Y, Wei Y, Zhang P, Rezaeian AH, Teruya-Feldstein J, et al. LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med. 2012;18:1511–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Iorns E, Ward TM, Dean S, Jegg A, Thomas D, Murugaesu N, et al. Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor. Breast Cancer Res Treat. 2012;135:79–91.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol. 2016;18:1078–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng H, Qu J, Jin N, Xu J, Lin C, Chen Y, et al. Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer. Cancer Cell. 2016;30:459–73.

    Article  CAS  PubMed  Google Scholar 

  14. Yoneda T, Sasaki A, Mundy GR. Osteolytic bone metastasis in breast cancer. Breast Cancer Res Treat. 1994;32:73–84.

    Article  CAS  PubMed  Google Scholar 

  15. Campbell JP, Merkel AR, Masood-Campbell SK, Elefteriou F, Sterling JA. Models of bone metastasis. J Vis Exp. 2012;67:e4260.

    Google Scholar 

  16. Huang G, Yan H, Ye S, Tong C, Ying Q-L. STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells. 2014;32:1149–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Harhous Z, Booz GW, Ovize M, Bidaux G, Kurdi M. An update on the multifaceted roles of STAT3 in the heart. Front Cardiovasc Med. 2019;6:150.

  18. Wang X-j, Qiao Y, Xiao MM, Wang L, Chen J, Lv W, et al. Opposing roles of acetylation and phosphorylation in LIFR-dependent self-renewal growth signaling in mouse embryonic stem cells. Cell Rep. 2017;18:933–46.

    Article  CAS  PubMed  Google Scholar 

  19. Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, et al. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLoS ONE. 2012;7:e35569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, et al. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat Cell Biol. 2013;15:1351–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, et al. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 2009;69:836–44.

    Article  CAS  PubMed  Google Scholar 

  22. Almog N, Briggs C, Beheshti A, Ma L, Wilkie KP, Rietman E, et al. Transcriptional changes induced by the tumor dormancy-associated microRNA-190. Transcription. 2013;4:177–91.

    Article  PubMed  CAS  Google Scholar 

  23. Oki T, Nishimura K, Kitaura J, Togami K, Maehara A, Izawa K, et al. A novel cell-cycle-indicator, mVenus-p27K-, identifies quiescent cells and visualizes G0-G1 transition. Sci Rep. 2014;4:4012–4012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Pernodet N, Hermetet F, Adami P, Vejux A, Descotes F, Borg C, et al. High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients. Breast Cancer Res. 2012;14:R136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gawrzak S, Rinaldi L, Gregorio S, Arenas EJ, Salvador F, Urosevic J, et al. MSK1 regulates luminal cell differentiation and metastatic dormancy in ER+ breast cancer. Nat Cell Biol. 2018;20:211–21.

    Article  CAS  PubMed  Google Scholar 

  26. Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature. 2012;483:598–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yumoto K, Eber MR, Wang J, Cackowski FC, Decker AM, Lee E, et al. Axl is required for TGF-beta2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep. 2016;6:36520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bos PD, Zhang XHF, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cohen AL, Neumayer L, Boucher K, Factor RE, Shrestha G, Wade M, et al. Window-of-opportunity study of valproic acid in breast cancer testing a gene expression biomarker. JCO Precis Oncol. 2017;1:1–11.

    Google Scholar 

  31. Abaza M-SI, Bahman A-M, Al-Attiyah RaJ. Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms. Int J Mol Med. 2014;34:513–32.

    Article  CAS  PubMed  Google Scholar 

  32. Connolly RM, Li H, Jankowitz RC, Zhang Z, Rudek MA, Jeter SC, et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a Phase II National Cancer Institute/Stand Up to Cancer Study. Clin Cancer Res. 2017;23:2691–701.

    Article  CAS  PubMed  Google Scholar 

  33. Clements ME, Johnson RW. Breast cancer dormancy in bone. Curr Osteoporos Rep. 2019;17:353–61.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cackowski FC, Eber MR, Rhee J, Decker AM, Yumoto K, Berry JE, et al. Mer tyrosine kinase regulates disseminated prostate cancer cellular dormancy. J Cell Biochem. 2017;118:891–902.

    Article  CAS  PubMed  Google Scholar 

  35. Yu-Lee LY, Yu G, Lee YC, Lin SC, Pan J, Pan T, et al. Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGFbetaRIII-p38MAPK-pS249/T252RB pathway. Cancer Res. 2018;78:2911–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carlson P, Dasgupta A, Grzelak CA, Kim J, Barrett A, Coleman IM, et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol. 2019;21:238–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16:67–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. El Touny LH, Vieira A, Mendoza A, Khanna C, Hoenerhoff MJ, Green JE. Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells. J Clin Investig. 2014;124:156–68.

    Article  CAS  PubMed  Google Scholar 

  39. Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L, Hunter T. Urokinase receptor and fibronectin regulate the ERKMAPK to p38MAPK activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell. 2001;12:863–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, et al. NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes. Nat Commun. 2015;6:6170.

    Article  CAS  PubMed  Google Scholar 

  41. Douglas AM, Goss GA, Sutherland RL, Hilton DJ, Berndt MC, Nicola NA, et al. Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Oncogene. 1997;14:661.

    Article  CAS  PubMed  Google Scholar 

  42. Douglas AM, Grant SL, Gross GA, Clouston DR, Sutherland RL, Begley CG. Oncostatin M induces the differentiation of breast cancer cells. Int J Cancer. 1998;75:64–73.

    Article  CAS  PubMed  Google Scholar 

  43. Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363:15–23.

    Article  CAS  PubMed  Google Scholar 

  44. Morris VL, Tuck AB, Wilson SM, Percy D, Chambers AF. Tumor progression and metastasis in murine D2 hyperplastic alveolar nodule mammary tumor cell lines. Clin Exp Metastasis. 1993;11:103–12.

    Article  CAS  PubMed  Google Scholar 

  45. Kusuma N, Burrows A, Ling X, Jupp L, Anderson RL, Pouliot N. Bone-derived soluble factors and laminin-511 cooperate to promote migration, invasion and survival of bone-metastatic breast tumor cells AU - Denoyer, Delphine. Growth Factors. 2014;32:63–73.

    Article  PubMed  CAS  Google Scholar 

  46. Clements ME, Johnson RW. PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells. Oncogene. 2020;39:1318–34.

    Article  CAS  PubMed  Google Scholar 

  47. Johnson RW, Sun Y, Ho PWM, Chan ASM, Johnson JA, Pavlos NJ, et al. Parathyroid hormone-related protein negatively regulates tumor cell dormancy genes in a PTHR1/cyclic AMP-independent manner. Front Endocrinol. 2018;9:241.

    Article  Google Scholar 

  48. Formisano L, Stauffer KM, Young CD, Bhola NE, Guerrero-Zotano AL, Jansen VM, et al. Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER+ Breast Cancer [published correction appears in Clin Cancer Res. 2019 Feb 15;25(4):1433]. Clin Cancer Res. 2017;23:6138–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge Mr. Joshua Johnson for histological processing and sectioning, and Dr. Vered Stearns and her team at Johns Hopkins for their assistance in accessing the clinical patient data. Samples from Phase II clinical trial of entinostat and azacitidine [33] were obtained, thanks to the Cancer Therapy Evaluation Program, National Cancer Institute (MCR-0019-P2C, U01CA070095, and UM1CA186691). We thank the NCI Cancer Therapy Evaluation Program (CTEP), Stand Up to Cancer and the American Association for Cancer Research, Celgene Corporation and Syndax Pharmaceuticals, Lee Jeans and the Entertainment Industry Foundation (EIF), and the research teams and physicians at participating sites. Flow Cytometry experiments were performed in the VMC Flow Cytometry Shared Resource, which is supported by the Vanderbilt-Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404).

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Authors and Affiliations

  1. Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA

    Miranda E. Clements, Courtney Edwards, Vera Todd & Rachelle W. Johnson

  2. Vanderbilt Center for Bone Biology, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Miranda E. Clements, Lauren Holtslander, Courtney Edwards, Vera Todd, Kennady Bullock & Rachelle W. Johnson

  3. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Lauren Holtslander & Rachelle W. Johnson

  4. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, USA

    Samuel D. R. Dooyema

  5. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Kennady Bullock & Kensey Bergdorf

  6. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Cynthia A. Zahnow

  7. Cancer Research@UCC, College of Medicine and Health, University College Cork, Cork, Ireland

    Roisin M. Connolly

  8. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA

    Roisin M. Connolly

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Contributions

MEC and RWJ conceptualized the project and developed the methodologies. MEC, LH, CE, VT, SDRD, K Bullock, K Bergdorf, and R.M.C. performed the experiments. MEC and RWJ wrote, edited, and reviewed the manuscript.

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Correspondence to Rachelle W. Johnson.

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MEC, LH, CE, and RWJ are supported by DoD Breakthrough Award W81XWH-18-1-0029 (RWJ), and VT and RWJ are supported by NIH award R00CA194198 (RWJ). This project was also supported by scholarship funds from NIH award P30CA068485 Vanderbilt-Ingram Cancer Center Support Grant. RMC has received research grants to institution from Novartis, Puma Biotechnology, Merck, Genentech, and Macrogenics.

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Clements, M.E., Holtslander, L., Edwards, C. et al. HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene 40, 5314–5326 (2021). https://doi.org/10.1038/s41388-021-01931-1

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