Skip to main content

Advertisement

SpringerLink
Log in

Plasma apolipoprotein M predicts overall survival in metastatic breast cancer patients

  • Original Laboratory Investigation
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Apolipoprotein M (APOM) is a plasma apolipoprotein closely involved with lipid metabolism and inflammation. In vitro studies suggest that APOM may also have a tumor-suppressive role in breast cancer. In the present study, we aimed to evaluate the impact of plasma APOM levels on the prognosis of breast cancer patients.

Methods

We measured APOM levels using an enzyme-linked immunosorbent assay in 75 patients with ER-positive/HER2-negative metastatic breast cancer. The endpoint was overall survival (OS) at 24 months.

Results

During the 24-month follow-up period, 34.7% of the patients died. Baseline APOM levels were significantly reduced in patients who deceased during follow-up compared to survivors (42.7 ± 14.5 µg/mL versus 52.2 ± 13.8 µg/mL; P = 0.003). Cox regression analysis showed a hazard ratio of 0.30 [95% confidence interval 0.15–0.61]; P < 0.001 per doubling of APOM levels. Correction for age, C-reactive protein, menopausal state, histology of the primary tumor, metastatic site, number of metastases, endocrine resistance, scheduled therapy line, and kind of scheduled therapy indicated that circulating APOM predicted OS independently of these parameters (HRper doubling = 0.23 [0.09–0.56; P = 0.001).

Conclusions

Our study suggests that circulating APOM is significantly linked with reduced mortality in metastatic breast cancer patients.

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

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/CAAC.21492

    Article  PubMed  Google Scholar 

  2. Cardoso F, Costa A, Senkus E et al (2017) 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol 28:3111. https://doi.org/10.1093/ANNONC/MDX036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Burstein HJ, Somerfield MR, Barton DL et al (2021) Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol 39:3959–3977. https://doi.org/10.1200/JCO.21.01392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu N, Dahlbäck B (1999) A novel human apolipoprotein (apoM). J Biol Chem 274:31286–31290. https://doi.org/10.1074/JBC.274.44.31286

    Article  CAS  PubMed  Google Scholar 

  5. Obinata H, Hla T (2012) Sphingosine 1-phosphate in coagulation and inflammation. Semin Immunopathol 34:73. https://doi.org/10.1007/S00281-011-0287-3

    Article  CAS  PubMed  Google Scholar 

  6. Therond P, Chapman MJ (2022) Sphingosine-1-phosphate: metabolism, transport, atheroprotection and effect of statin treatment. Curr Opin Lipidol 33:199–207. https://doi.org/10.1097/MOL.0000000000000825

    Article  CAS  PubMed  Google Scholar 

  7. Ruiz M, Frej C, Holmér A et al (2017) High-density lipoprotein-associated apolipoprotein M limits endothelial inflammation by delivering sphingosine-1-phosphate to the sphingosine-1-phosphate receptor 1. Arterioscler Thromb Vasc Biol 37:118–129

    Article  CAS  PubMed  Google Scholar 

  8. Zhang XY, Dong X, Zheng L et al (2003) Specific tissue expression and cellular localization of human apolipoprotein M as determined by in situ hybridization. Acta Histochem 105:67–72. https://doi.org/10.1078/0065-1281-00687

    Article  CAS  PubMed  Google Scholar 

  9. Bai Y, Pei W, Zhang X et al (2021) ApoM is an important potential protective factor in the pathogenesis of primary liver cancer. J Cancer 12:4661. https://doi.org/10.7150/JCA.53115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou Y, Yao S, Yu M et al (2022) The effects and possible mechanism of action of apolipoprotein M on the growth of breast cancer cells. Mol Biol Rep 49:1171–1179. https://doi.org/10.1007/S11033-021-06945-2

    Article  CAS  PubMed  Google Scholar 

  11. Györffy B, Lanczky A, Eklund AC et al (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat 123:725–731. https://doi.org/10.1007/S10549-009-0674-9

    Article  PubMed  Google Scholar 

  12. Youden WJ (1950) Index for rating diagnostic tests. Cancer. 3:32

    Article  CAS  PubMed  Google Scholar 

  13. Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191. https://doi.org/10.3758/BF03193146

    Article  PubMed  Google Scholar 

  14. Zhang X, Bai Y, Zhu W et al (2022) ApoM regulates PFKL through the transcription factor SREBF1 to inhibit the proliferation, migration and metastasis of liver cancer cells. Oncol Lett. https://doi.org/10.3892/OL.2022.13331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xue H, Yu M, Zhou Y et al (2020) Apolipoprotein M inhibits proliferation and migration of larynx carcinoma cells. Sci Rep. https://doi.org/10.1038/S41598-020-76480-W

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu MM, Yao S, Luo KM et al (2017) Apolipoprotein M increases the expression of vitamin D receptor mRNA in colorectal cancer cells detected with duplex fluorescence reverse transcription-quantitative polymerase chain reaction. Mol Med Rep 16:1167–1172. https://doi.org/10.3892/MMR.2017.6716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bao J, Zhu L, Zhu Q et al (2016) SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer. Oncol Lett 12:2409–2416. https://doi.org/10.3892/OL.2016.4988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huss L, Butt ST, Borgquist S et al (2019) Vitamin D receptor expression in invasive breast tumors and breast cancer survival. Breast Cancer Res. https://doi.org/10.1186/S13058-019-1169-1

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhu Y, Luo G, Jiang B et al (2018) Apolipoprotein M promotes proliferation and invasion in non-small cell lung cancers via upregulating S1PR1 and activating the ERK1/2 and PI3K/AKT signaling pathways. Biochem Biophys Res Commun 501:520–526. https://doi.org/10.1016/J.BBRC.2018.05.029

    Article  CAS  PubMed  Google Scholar 

  20. Mu Q, Luo G, Wei J et al (2021) Apolipoprotein M promotes growth and inhibits apoptosis of colorectal cancer cells through upregulation of ribosomal protein S27a. EXCLI J. 20:145–159. https://doi.org/10.17179/EXCLI2020-2867

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nielsen LB, Christoffersen C, Ahnström J, Dahlbäck B (2009) ApoM: gene regulation and effects on HDL metabolism. Trends Endocrinol Metab 20:66–71. https://doi.org/10.1016/J.TEM.2008.11.003

    Article  CAS  PubMed  Google Scholar 

  22. Cheng G, Zheng L (2022) Regulation of the apolipoprotein M signaling pathway: a review. J Recept Signal Transduct Res 42:285–292. https://doi.org/10.1080/10799893.2021.1924203

    Article  CAS  PubMed  Google Scholar 

  23. Zheng Z, Zeng Y, Zhu X et al (2019) ApoM-S1P modulates Ox-LDL-induced inflammation through the PI3K/Akt signaling pathway in HUVECs. Inflammation 42:606–617. https://doi.org/10.1007/S10753-018-0918-0

    Article  CAS  PubMed  Google Scholar 

  24. Gao JJ, Hu YW, Wang YC et al (2015) ApoM suppresses TNF-α-induced expression of ICAM-1 and VCAM-1 through inhibiting the activity of NF-κB. DNA Cell Biol 34:550–556. https://doi.org/10.1089/DNA.2015.2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi Y, Liu H, Liu H et al (2020) Increased expression levels of inflammatory cytokines and adhesion molecules in lipopolysaccharide-induced acute inflammatory apoM-/- mice. Mol Med Rep 22:3117–3126. https://doi.org/10.3892/MMR.2020.11426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia L, Tan S, Zhou Y et al (2018) Role of the NFκB-signaling pathway in cancer. Onco Targets Ther 11:2063–2073. https://doi.org/10.2147/OTT.S161109

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kumaraswamy SB, Linder A, Åkesson P, Dahlbäck B (2012) Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes. Crit Care. https://doi.org/10.1186/CC11305

    Article  PubMed  PubMed Central  Google Scholar 

  28. Feingold KR, Shigenaga JK, Chui LG et al (2008) Infection and inflammation decrease apolipoprotein M expression. Atherosclerosis 199:19–26. https://doi.org/10.1016/J.ATHEROSCLEROSIS.2007.10.007

    Article  CAS  PubMed  Google Scholar 

  29. Mosialou I, Krasagakis K, Kardassis D (2011) Opposite regulation of the human apolipoprotein M gene by hepatocyte nuclear factor 1 and Jun transcription factors. J Biol Chem 286:17259–17269. https://doi.org/10.1074/JBC.M110.200659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mosialou I, Zannis VI, Kardassis D (2010) Regulation of human apolipoprotein m gene expression by orphan and ligand-dependent nuclear receptors. J Biol Chem 285:30719–30730. https://doi.org/10.1074/JBC.M110.131771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen J, Pan Y, He B et al (2018) Meta-analysis of prognostic value of inflammation parameter in breast cancer. J Cancer Res Ther 14:S85–S89. https://doi.org/10.4103/0973-1482.160917

    Article  PubMed  Google Scholar 

  32. Dethlefsen C, Højfeldt G, Hojman P (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138:657–664. https://doi.org/10.1007/S10549-013-2488-Z

    Article  CAS  PubMed  Google Scholar 

  33. Mikkelsen MK, Lindblom NAF, Dyhl-Polk A et al (2022) Systematic review and meta-analysis of C-reactive protein as a biomarker in breast cancer. Crit Rev Clin Lab Sci 59:480–500. https://doi.org/10.1080/10408363.2022.2050886

    Article  CAS  PubMed  Google Scholar 

  34. Liu M, Frej C, Langefeld CD et al (2019) Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus. J Lipid Res 60:1425–1431. https://doi.org/10.1194/JLR.P089409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ahnström J, Gottsäter A, Lindblad B, Dahlbäck Björn B (2010) Plasma concentrations of apolipoproteins A-I, B, and M in patients with critical limb ischemia. Clin Biochem 43:599–603. https://doi.org/10.1016/J.CLINBIOCHEM.2010.01.001

    Article  PubMed  Google Scholar 

  36. Chirinos JA, Zhao L, Jia Y et al (2020) Reduced apolipoprotein M and adverse outcomes across the spectrum of human heart failure. Circulation 141:1463–1476. https://doi.org/10.1161/CIRCULATIONAHA.119.045323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hart CD, Migliaccio I, Malorni L et al (2015) Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol 12:541–552. https://doi.org/10.1038/NRCLINONC.2015.99

    Article  PubMed  Google Scholar 

Download references

Funding

This present study was partly financed by the European Regional Development Fund through the INTERREG V program ‘Alpenrhein-Bodensee-Hochrein,’ project number: ABH055.

Author information

Authors and Affiliations

  1. Vorarlberg Institute for Vascular Investigation and Treatment Laboratory, Stadtstrasse 33, 6850, Dornbirn, Austria

    Axel Muendlein, Christine Heinzle, Eva Maria Brandtner, Andreas Leiherer, Kathrin Geiger, Stella Gaenger & Heinz Drexel

  2. Medical Central Laboratories, Feldkirch, Austria

    Christine Heinzle, Andreas Leiherer & Kathrin Geiger

  3. Drexel University College of Medicine, Philadelphia, PA, USA

    Heinz Drexel

  4. Onkologie Ravensburg, Ravensburg, Germany

    Tobias Dechow & Thomas Decker

Authors
  1. Axel Muendlein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Heinzle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva Maria Brandtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Leiherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathrin Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stella Gaenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heinz Drexel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tobias Dechow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Decker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Conception and design of the study were performed by TD and AM. Patients’ recruitment, sample, and data collection were carried out by TD, TD, KG, and SG. Material preparation, sample analysis, and data analysis were performed by CH, EMB, HD, and AL. The first draft of the manuscript was written by AM and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Axel Muendlein.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the State Chamber of Medicine of Baden-Württemberg (F-2017-046).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 252 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muendlein, A., Heinzle, C., Brandtner, E.M. et al. Plasma apolipoprotein M predicts overall survival in metastatic breast cancer patients. Breast Cancer Res Treat 201, 571–576 (2023). https://doi.org/10.1007/s10549-023-07045-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-023-07045-4

Keywords

Search

Navigation