Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer

Oncogene volume 42, pages 2402–2414 (2023)Cite this article

Subjects

Abstract

The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPARγ dependent; deletion of PPARγ in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells. Loss of PPARγ expression in mammary epithelium of obese mice increased expression of 2-aminoadipate semialdehyde synthase (AASS) which regulates lysine catabolism to acetoacetate. PPARγ-associated co-repressors and activators regulated AASS expression via a canonical response element. AASS expression was significantly reduced in human breast cancer, and AASS overexpression or acetoacetate treatment inhibited proliferation and induced autophagy and senescence in human breast cancer cell lines. Genetic or pharmacologic HDAC inhibition promoted autophagy and senescence in mammary tumor cells in vitro and in vivo. We concluded that lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Increased mammary tumor latency, LP cell depletion, decreased proliferation, and increased apoptosis in MMTV-Cre;ppargf/f;mc4r−/−;Wnt mice.
Fig. 2: MMTV-Cre;ppargf/f;mc4r−/−;Wnt mammary tumors exhibit cytostatic autophagy and senescence.
Fig. 3: Increased AASS expression and acetoacetate levels in mammary tumors from MMTV-Cre;ppargf/f;mc4r−/−;Wnt mice.
Fig. 4: PPARγ repressor complex inhibits AASS gene activation in obese mammary tumors.
Fig. 5: Decreased AASS expression in human breast cancer.
Fig. 6: Reduced HDAC3 expression inhibits mammary tumorsphere proliferation and induces autophagy and senescence.
Fig. 7: HDAC inhibition reduces cell proliferation and depletes the LP cell fraction in obese mammary tumors.
Fig. 8: The HDAC inhibitor vorinostat induces autophagy and senescence in mc4r−/−;Wnt mammary tumors.

Similar content being viewed by others

Data availability

Data are available on reasonable request from the authors.

References

  1. American Cancer Society. Current year estimates for breast cancer. 2021. Cancer.org.

  2. Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer. 2018;119:141–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dawson SJ, Rueda OM, Aparicio S, Caldas C. A new genome driven integrated classification of breast cancer and its implications. EMBO J. 2013;32:617–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid activated nuclear receptors. Nature. 2008;454:470–7.

    Article  CAS  PubMed  Google Scholar 

  5. Vona-Davis L, Rose DP. The obesity-inflammation-eicosanoid axis in breast cancer. J Mamm Gl Biol Neopl. 2013;18:291–307.

    Article  Google Scholar 

  6. Youssef J, Badr M. Peroxisome proliferator activated receptors and cancer: challenges and opportunities. Br J Pharmacol. 2011;164:68–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jiang WG, Douglas-Jones A, Mansel RE. Expression of peroxisome proliferator activated receptor γ (PPARγ) and the PPARγ coactivator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer. 2003;106:752–7.

    Article  CAS  PubMed  Google Scholar 

  8. Kramer K, Wu J, Crowe DL. Tumor suppressor control of the cancer stem cell niche. Oncogene. 2016;35:4165–78.

    Article  CAS  PubMed  Google Scholar 

  9. Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, et al. American Cancer Society guidelines on nutrition and physical activity for cancer prevention. CA Cancer J Clin. 2012;62:30–67.

    Article  PubMed  Google Scholar 

  10. Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and inflammation: new insights into breast cancer development and progression. Am Soc Clin Oncol Educ Book. 2013;33:45–51.

    Article  Google Scholar 

  11. Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular pathways: adipose inflammation as a mediator of obesity associated cancer. Clin Cancer Res. 2013;19:6074–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ligibel JA, Strickler HD. Obesity and its impact on breast cancer: tumor incidence, recurrence, survival, and possible interventions. Am Soc Clin Oncol Educ Book. 2013;33:52–9.

    Article  Google Scholar 

  13. Rose DP, Vona-Davis L. Biochemical and molecular mechanisms for the association between obesity, chronic inflammation, and breast cancer. Biofactors. 2014;40:1–12.

    Article  CAS  PubMed  Google Scholar 

  14. Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, et al. Effect of obesity on prognosis after early stage breast cancer. J Clin Oncol. 2011;29:25–31.

    Article  PubMed  Google Scholar 

  15. von Drygalski A, Tran TB, Messer K, Pu M, Corringham S, Nelson C, et al. Obesity is an independent predictor of poor survival in metastatic breast cancer: retrospective analysis of a patient cohort whose treatment included high dose chemotherapy and autologous stem cell support. Int J Breast Cancer. 2011;2011:523276.

    Google Scholar 

  16. Davis AA, Kaklamani VG. Metabolic syndrome and triple negative breast cancer: a new paradigm. Int J Breast Cancer. 2012;2012:809291.

    Article  PubMed  Google Scholar 

  17. van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479:189–95.

    Article  PubMed  Google Scholar 

  18. Shehata M, Teschendorff A, Sharp G, Novcic N, Russell IA, Avril S, et al. Phenotypic and functional characterization of the luminal cell hierarchy of the mammary gland. Breast Cancer Res. 2012;14:134–52.

    Article  Google Scholar 

  19. Sauer SW, Opp S, Hoffmann GF, Koeller DM, Okun JG, Kolker S. Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I. Brain. 2011;134:157–70.

    Article  PubMed  Google Scholar 

  20. Lavallard VJ, Meijer AJ, Codogno P, Gual P. Autophagy, signaling, and obesity. Pharmacol Res. 2012;66:513–25.

    Article  CAS  PubMed  Google Scholar 

  21. Jain K, Paranandi KS, Sridharan S, Basu A. Autophagy in breast cancer and its implications for therapy. Am J Cancer Res. 2013;3:251–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Maycotte P, Thorburn A. Targeting autophagy in breast cancer. World J Clin Oncol. 2014;5:224–40.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chen S, Jiang YZ, Huang L, Zhou RJ, Yu KD, Liu Y, et al. The residual tumor autophagy marker LC3B serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy. Clin Cancer Res. 2013;19:6853–62.

    Article  CAS  PubMed  Google Scholar 

  24. Gewirtz DA. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74:647–51.

    Article  CAS  PubMed  Google Scholar 

  25. Capparelli C, Guido C, Whitaker-Menezes D, Bonuccelli G, Balliet R, Pestell TG, et al. Autophagy and senescence in cancer associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle. 2012;11:2285–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Avena P, Anselmo W, Whitaker-Menezes D, Wang C, Pestell RG, Lamb RS, et al. Compartment specific activation of PPARγ governs breast cancer tumor growth via metabolic reprogramming and symbiosis. Cell Cycle. 2013;12:1360–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Capparelli C, Chiavarina B, Whitaker-Menezes D, Pestell TG, Pestell RG, Hulit J, et al. Cdk inhibitors (p16/p19/p21) induce senescence and autophagy in cancer associated fibroblasts fueling tumor growth via paracrine interactions without an increase in neo-angiogenesis. Cell Cycle. 2012;11:3599–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brown NE, Jeselsohn R, Bihani T, Hu MG, Foltopoulou P, Kuperwasser C, et al. Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Res. 2012;72:6477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bertucci F, Ng CKY, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569:560–4.

    Article  CAS  PubMed  Google Scholar 

  30. van Geelen CT, Savas P, Teo ZL, Luen SJ, Weng CF, Ko YA, et al. Clinical indications of prospective genomic profiling of metastatic breast cancer patients. Breast Cancer Res. 2020;22:91.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rovito D, Gionfriddo G, Barone I, Giordano C, Grande F, De Amicis F, et al. Ligand activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression. Oncotarget. 2016;7:65109–24.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Cui Z, Xie M, Wu Z, Shi Y. Relationship between histone deacetylase 3 (HDAC3) and breast cancer. Med Sci Monitor. 2018;24:2456–64.

    Article  CAS  Google Scholar 

  33. Ramadan WS, Talaat IM, Hachim MY, Lischka A, Gemoll T, El-Awady R. The impact of CBP expression in estrogen receptor positive breast cancer. Clin Epigenet. 2021;13:72.

    Article  CAS  Google Scholar 

  34. Finn PF, Dice JF. Ketone bodies stimulate chaperone mediated autophagy. J Biol Chem. 2005;280:25864–70.

    Article  CAS  PubMed  Google Scholar 

  35. Rojas-Morales P, Tapia E, Pedraza-Chaverri J. β-hydroxybutyrate: a signaling metabolite in starvation response. Cell Signal. 2016;28:917–23.

    Article  CAS  PubMed  Google Scholar 

  36. Huang YH, Yang PM, Chuah QY, Lee YJ, Hsieh YF, Peng CW, et al. Autophagy promotes radiation induced senescence but inhibits bystander effects in human breast cancer cells. Autophagy. 2014;10:1212–28.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sharma K, Goehe RW, Di X, Hicks MA, Torti SV, Torti FM, et al. A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D analog EB1089. Autophagy. 2014;10:2346–61.

    Article  CAS  PubMed  Google Scholar 

  38. Wilson EN, Bristol ML, Di X, Maltese WA, Koterba K, Beckman MJ, et al. A switch between cytoprotective and cytotoxic autophagy in the radiosensitization of breast tumor cells by chloroquine and vitamin D. Horm Cancer. 2011;2:272–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhao Y, He J, Yang L, Luo Q, Liu Z. Histone deacetylase 3 modification of microRNA-31 promotes cell proliferation and aerobic glycolysis in breast cancer and is predictive of poor prognosis. J Breast Cancer. 2018;21:112–23.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Palmieri D, Lockman PR, Thomas FC, Hua E, Herring J, Hargrave E, et al. Vorinostat inhibits brain metastatic colonization in a model of triple negative breast cancer and induces DNA double strand breaks. Clin Cancer Res. 2009;15:6148–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Cremoux P, Dalyai M, N’Dove O, Moutahir F, Rolland G, Chouchane-Mik O, et al. HDAC inhibition does not induce estrogen receptor in human triple negative breast cancer cell lines and patient derived xenografts. Breast Cancer Res Treat. 2015;149:81–9.

    Article  PubMed  Google Scholar 

  42. Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devarai SG, et al. Histone deacetylase inhibitor treatment induces BRCAness and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget. 2014;5:5637–50.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Vasilatos SN, Katz TA, Oesterreich S, Wan Y, Davidson NE, Huang Y. Crosstalk between lysine specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis. 2013;34:1196–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tu Y, Hershman DL, Bhalla K, Fiskus W, Pellegrino CM, Andreopoulou E, et al. A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer. Breast Cancer Res Treat. 2014;146:145–52.

    Article  CAS  PubMed  Google Scholar 

  45. Wang J, Kim TH, Ahn MY, Lee J, Jung JH, Choi WS, et al. Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF7 human breast cancer cells. Int J Oncol. 2012;41:1101–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs. Ke Ma, Balaji Ganesh, Hui Chen, and Feigen Seiler (University of Illinois Research Resources Center) for assistance with confocal microscopy, flow cytometry, mass spectrometry, and electron microscopy. This study was supported by Department of Defense Breast Cancer Research Program Award W81XWH-20-1-0029.

Author information

Authors and Affiliations

  1. University of Illinois Cancer Center, 801 S. Paulina Street, Room 525, Chicago, IL, 60612, USA

    Jianchun Wu, Kaitrin Kramer & David L. Crowe

Authors
  1. Jianchun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaitrin Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. Crowe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JW and KK performed experiments and analyzed data. DLC supervised the project and wrote the manuscript.

Corresponding author

Correspondence to David L. Crowe.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

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

Wu, J., Kramer, K. & Crowe, D.L. Lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer. Oncogene 42, 2402–2414 (2023). https://doi.org/10.1038/s41388-023-02766-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02766-8

Search

Advanced search

Quick links