Skip to main content

Advertisement

SpringerLink
Log in

Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

A perennial challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues. The protection of cell viability observed with CD47 is mediated autonomously by activation of protective autophagy. However, whether CD47 protects cancer cells from cytotoxic chemotherapy is unknown.

Methods

We tested the effect of CD47 blockade on cancer cell survival using a 2-dimensional high-throughput cell proliferation assay in 4T1 breast cancer cell lines. To evaluate blockade of CD47 in combination with chemotherapy in vivo, we employed the 4T1 breast cancer model and examined tumor and cardiac tissue viability as well as autophagic flux.

Results

Our high-throughput screen revealed that blockade of CD47 does not interfere with the cytotoxic activity of anthracyclines against 4T1 breast cancer cells. Targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an anti-tumor innate immune response. Moreover, systemic suppression of CD47 protected cardiac tissue viability and function in mice treated with doxorubicin.

Conclusions

Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, the absence of CD47 in did not elicit a protective effect in cancer cells, but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AC :

Activity of maximum concentration

CD :

Cluster of differentiation

CD47 (−) :

CD47 deficient

CD47M :

CD47 morpholino

CRC :

Concentration response curves

DMEM :

Dulbecco’s modified eagle medium

DOX :

Doxorubicin

DAMPs :

Damage-associated molecular patterns

HIF1 :

Hypoxia-inducible factor 1

SIRPα :

Signal regulatory protein alpha

UPR :

Unfolded protein response

WT :

Wild type

References

  1. Herrmann J, Lerman A, Sandhu NP, Villarraga HR, Mulvagh SL, Kohli M (2014) Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc 89(9):1287–1306

    Article  Google Scholar 

  2. Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, Degraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD (2009) Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci Transl Med 1(3):3ra7

    Article  Google Scholar 

  3. Soto-Pantoja DR, Ridnour LA, Wink DA, Roberts DD (2013) Blockade of CD47 increases survival of mice exposed to lethal total body irradiation. Sci Rep 3:1038

    Article  Google Scholar 

  4. Lo J, Lau EY, So FT, Lu P, Chan VS, Cheung VC, Ching RH, Cheng BY, Ma MK, Ng IO et al (2016) Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int 36(5):737–745

    Article  CAS  Google Scholar 

  5. Samanta D, Park Y, Ni X, Li H, Zahnow CA, Gabrielson E, Pan F, Semenza GL (2018) Chemotherapy induces enrichment of CD47(+)/CD73(+)/PDL1(+) immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci USA 115(6):E1239–E1248

    Article  Google Scholar 

  6. Soto-Pantoja DR, Kaur S, Roberts DD (2015) CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol 50(3):212–230

    Article  CAS  Google Scholar 

  7. Soto Pantoja DR, Miller TW, Pendrak ML, DeGraff WG, Sullivan C, Ridnour LA, Abu-Asab M, Wink DA, Tsokos M, Roberts DD (2012) CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8(11):0–1

    Article  CAS  Google Scholar 

  8. Soto-Pantoja DR, Stein EV, Rogers NM, Sharifi-Sanjani M, Isenberg JS, Roberts DD (2013) Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin Ther Targets 17(1):89–103

    Article  CAS  Google Scholar 

  9. Soto-Pantoja DR, Terabe M, Ghosh A, Ridnour LA, DeGraff WG, Wink DA, Berzofsky JA, Roberts DD (2014) CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res 74(23):6771–6783

    Article  CAS  Google Scholar 

  10. Turner N, Biganzoli L, Di Leo A (2015) Continued value of adjuvant anthracyclines as treatment for early breast cancer. Lancet Oncol 16(7):e362–e369

    Article  Google Scholar 

  11. Early Breast Cancer Trialists’ Collaborative G, Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P et al (2012) Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379(9814):432–444

    Article  Google Scholar 

  12. Coombes RC, Bliss JM, Wils J, Morvan F, Espie M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A et al (1996) Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol 14(1):35–45

    Article  CAS  Google Scholar 

  13. Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B et al (2007) Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer 43(5):877–884

    Article  CAS  Google Scholar 

  14. Hamilton DH, Matthews Griner L, Keller JM, Hu X, Southall N, Marugan J, David JM, Ferrer M, Palena C (2016) Targeting estrogen receptor signaling with fulvestrant enhances immune and chemotherapy-mediated cytotoxicity of human lung cancer. Clin Cancer Res

  15. Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP (2006) Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci USA 103(31):11473–11478

    Article  CAS  Google Scholar 

  16. Soto-Pantoja DR, Miller TW, Pendrak ML, DeGraff WG, Sullivan C, Ridnour LA, Abu-Asab M, Wink DA, Tsokos M, Roberts DD (2012) CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8(11):1628–1642

    Article  CAS  Google Scholar 

  17. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD et al (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci USA 109(17):6662–6667

    Article  CAS  Google Scholar 

  18. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167

    Article  Google Scholar 

  19. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG et al (2016) Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol 34(10):1134–1150

    Article  CAS  Google Scholar 

  20. Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, DeGraff WG, Tsokos M, Wink DA, Isenberg JS, Roberts DD (2009) Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Sci Transl Med 1:3ra7

    Article  Google Scholar 

  21. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685

    Article  CAS  Google Scholar 

  22. Yang S, Zhang JJ, Huang XY (2012) Mouse models for tumor metastasis. Methods Mol Biol 928:221–228

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Peper JK, Schuster H, Loffler MW, Schmid-Horch B, Rammensee HG, Stevanovic S (2014) An impedance-based cytotoxicity assay for real-time and label-free assessment of T-cell-mediated killing of adherent cells. J Immunol Methods 405:192–198

    Article  CAS  Google Scholar 

  24. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N et al (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13(1):54–61

    Article  CAS  Google Scholar 

  25. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 12(1):1–222

    Article  Google Scholar 

  26. Sawyer DB, Peng X, Chen B, Pentassuglia L, Lim CC (2010) Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis 53(2):105–113

    Article  CAS  Google Scholar 

  27. Suzuki S, Yokobori T, Tanaka N, Sakai M, Sano A, Inose T, Sohda M, Nakajima M, Miyazaki T, Kato H et al (2012) CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma. Oncol Rep 28(2):465–472

    Article  CAS  Google Scholar 

  28. Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY et al (2010) Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2(63):63ra94

    Article  CAS  Google Scholar 

  29. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138(2):286–299

    Article  CAS  Google Scholar 

  30. Nagahara M, Mimori K, Kataoka A, Ishii H, Tanaka F, Nakagawa T, Sato T, Ono S, Sugihara K, Mori M (2010) Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res 16(18):4625–4635

    Article  CAS  Google Scholar 

  31. Kaur S, Elkahloun AG, Singh SP, Chen QR, Meerzaman DM, Song T, Manu N, Wu W, Mannan P, Garfield SH et al (2016) A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget 7(9):10133–10152

    Article  Google Scholar 

  32. Bouguermouh S, Van VQ, Martel J, Gautier P, Rubio M, Sarfati M (2008) CD47 expression on T cell is a self-control negative regulator of type 1 immune response. J Immunol 180(12):8073–8082

    Article  CAS  Google Scholar 

  33. Ide K, Wang H, Tahara H, Liu J, Wang X, Asahara T, Sykes M, Yang YG, Ohdan H (2007) Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci USA 104(12):5062–5066

    Article  CAS  Google Scholar 

  34. Jaiswal S, Chao MP, Majeti R, Weissman IL (2010) Macrophages as mediators of tumor immunosurveillance. Trends Immunol 31(6):212–219

    Article  CAS  Google Scholar 

  35. Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill H, Presti J Jr, Chang HY, van de Rijn M et al (2009) Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA 106(33):14016–14021

    Article  CAS  Google Scholar 

  36. Soto-Pantoja DR, Isenberg JS, Roberts DD (2011) Therapeutic targeting of CD47 to modulate tissue responses to ischemia and radiation. J Genet Syndr Gene Ther 2(2)

  37. Isenberg JS, Annis DS, Pendrak ML, Ptaszynska M, Frazier WA, Mosher DF, Roberts DD (2009) Differential interactions of thrombospondin-1, -2, and -4 with CD47 and effects on cGMP signaling and ischemic injury responses. J Biol Chem 284(2):1116–1125

    Article  CAS  Google Scholar 

  38. Rath GM, Schneider C, Dedieu S, Rothhut B, Soula-Rothhut M, Ghoneim C, Sid B, Morjani H, El Btaouri H, Martiny L (2006) The C-terminal CD47/IAP-binding domain of thrombospondin-1 prevents camptothecin- and doxorubicin-induced apoptosis in human thyroid carcinoma cells. Biochimica et biophysica acta 1763(10):1125–1134

    Article  CAS  Google Scholar 

  39. Dutta D, Xu J, Kim JS, Dunn WA Jr, Leeuwenburgh C (2013) Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity. Autophagy 9(3):328–344

    Article  CAS  Google Scholar 

  40. Li DL, Wang ZV, Ding G, Tan W, Luo X, Criollo A, Xie M, Jiang N, May H, Kyrychenko V et al (2016) Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133(17):1668–1687

    Article  CAS  Google Scholar 

  41. Jangamreddy JR, Panigrahi S, Los MJ (2015) Monitoring of autophagy is complicated-salinomycin as an example. Biochimica et biophysica acta 1853(3):604–610

    Article  CAS  Google Scholar 

  42. White E (2007) Role of the metabolic stress responses of apoptosis and autophagy in tumor suppression. In: Ernst Schering Foundation symposium proceedings, pp 23–34

  43. Zhang X, Chen W, Fan J, Wang S, Xian Z, Luan J, Li Y, Wang Y, Nan Y, Luo M et al (2018) Disrupting CD47-SIRPalpha axis alone or combined with autophagy depletion for the therapy of glioblastoma. Carcinogenesis 39(5):689–699

    Article  Google Scholar 

  44. Denton D, Xu T, Kumar S (2015) Autophagy as a pro-death pathway. Immunol Cell Biol 93(1):35–42

    Article  CAS  Google Scholar 

  45. Guo B, Tam A, Santi SA, Parissenti AM (2016) Role of autophagy and lysosomal drug sequestration in acquired resistance to doxorubicin in MCF-7 cells. BMC Cancer 16(1):762

    Article  Google Scholar 

  46. White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15(17):5308–5316

    Article  Google Scholar 

  47. Liu Y, Levine B (2015) Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22(3):367–376

    Article  CAS  Google Scholar 

  48. Gewirtz DA (2014) The four faces of autophagy: implications for cancer therapy. Cancer Res 74(3):647–651

    Article  CAS  Google Scholar 

  49. Cook KL, Soto-Pantoja DR (2017) “UPRegulation” of CD47 by the endoplasmic reticulum stress pathway controls anti-tumor immune responses. Biomark Res 5:26

    Article  Google Scholar 

  50. Cook KL, Soto-Pantoja DR, Clarke PA, Cruz MI, Zwart A, Warri A, Hilakivi-Clarke L, Roberts DD, Clarke R (2016) Endoplasmic reticulum stress protein GRP78 modulates lipid metabolism to control drug sensitivity and antitumor immunity in breast cancer. Cancer Res 76(19):5657–5670

    Article  CAS  Google Scholar 

  51. Starobinets H, Ye J, Broz M, Barry K, Goldsmith J, Marsh T, Rostker F, Krummel M, Debnath J (2016) Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment. J Clin Invest 126(12):4417–4429

    Article  Google Scholar 

  52. Kroemer G, Galluzzi L (2017) Autophagy-dependent danger signaling and adaptive immunity to poorly immunogenic tumors. Oncotarget 8(4):5686–5691

    Article  Google Scholar 

  53. Montico B, Lapenta C, Ravo M, Martorelli D, Muraro E, Zeng B, Comaro E, Spada M, Donati S, Santini SM et al (2017) Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy. Oncoimmunology 6(11):e1356964

    Article  CAS  Google Scholar 

  54. Emens LA (2018) Breast cancer immunotherapy: facts and hopes. Clin Cancer Res 24(3):511–520

    Article  CAS  Google Scholar 

  55. Liu X, Pu Y, Cron K, Deng L, Kline J, Frazier WA, Xu H, Peng H, Fu YX, Xu MM (2015) CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21(10):1209–1215

    Article  CAS  Google Scholar 

  56. Zhang H, Lu H, Xiang L, Bullen JW, Zhang C, Samanta D, Gilkes DM, He J, Semenza GL (2015) HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci USA 112(45):E6215–E6223

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the statistical and editorial assistance of the Wake Forest Clinical and Translational Science Institute (WF CTSI), which is supported by NCATS, National Institutes of Health, through Grant Award Number UL1TR001420.

Funding

This work was supported by the NCI Career Development Award-K22 1K22CA181274-01A1 (DSP), Wake Forest Baptist Comprehensive Cancer Center’s NCI Cancer Center Support Grant P30CA012197 (DSP, KLC), the Intramural Research Program of the NIH/NCI (DDR) and The National Center for Advancing Translational Sciences (NCATS) (MF, CJT).

Author information

Author notes

  1. Yismeilin Feliz-Mosquea and Ashley A. Christensen have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Yismeilin R. Feliz-Mosquea, Ashley A. Christensen, Adam S. Wilson, Brian Westwood, Jasmina Varagic, Katherine L. Cook & David R. Soto-Pantoja

  2. Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Katherine L. Cook & David R. Soto-Pantoja

  3. Internal Medicine, Section on Cardiovascular Medicine, Pathology Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Giselle C. Meléndez

  4. Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Giselle C. Meléndez, Katherine L. Cook & David R. Soto-Pantoja

  5. Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Jasmina Varagic, Giselle C. Meléndez, Katherine L. Cook & David R. Soto-Pantoja

  6. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Anthony L. Schwartz, Maria J. Merino & David D. Roberts

  7. Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Qing-Rong Chen

  8. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA

    Lesley Mathews Griner, Rajarshi Guha, Craig J. Thomas & Marc Ferrer

Authors
  1. Yismeilin R. Feliz-Mosquea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashley A. Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adam S. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Westwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jasmina Varagic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giselle C. Meléndez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony L. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qing-Rong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lesley Mathews Griner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rajarshi Guha
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Craig J. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marc Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria J. Merino
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katherine L. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. David D. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David R. Soto-Pantoja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David R. Soto-Pantoja.

Ethics declarations

Conflict of interest

The authors of this manuscript have no conflicts of interest to report.

Ethical approval

Experiments in presented in this manuscript comply with the current laws of the United States of America and institutional research integrity policies. Tissue arrays from developed from tissues of human breast cancer patient sections analyzed in the Laboratory of Pathology National Cancer Institute, under approved protocol by the Institutional Review Board of the National Cancer Institute. Animal studies and procedures were approved by the Internal Animal Care and Use Committee (IACUC) of the NIH Intramural Research Program protocol # LP-012 and the Wake Forest IACUC protocol # A16-085. Other datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10549_2018_4884_MOESM1_ESM.jpg

Supplementary material 1 (JPEG 56 KB). Supplemental Figure 1: (A) immunohistochemical staining of human mammary gland (top) and human invasive breast cancer (representative of 5 cases) with human antibody B6H12 (brown stain). (B) LDH release assay in MDA-MB-231 cells. (C)Efficiency of CD47 knock down using anti-sense morpholino treatment in tumors N = 5, *p < 0.05.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feliz-Mosquea, Y.R., Christensen, A.A., Wilson, A.S. et al. Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy. Breast Cancer Res Treat 172, 69–82 (2018). https://doi.org/10.1007/s10549-018-4884-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-018-4884-x

Keywords

Search

Navigation