Skip to main content

Advertisement

SpringerLink
Log in

Breast Cancer, Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor Toward Exploring Their Possible Associations

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

A Correction to this article was published on 04 October 2021

This article has been updated

Abstract

Purpose

Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology.

Methods

We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues.

Results

GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070).

Conclusion

These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM 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
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due personal information protection but are available from the corresponding author on reasonable request.

Change history

References

  1. Lindsey AT, Freddie B, Rebecca LS, Jacques F, Joannie L-T, Ahmedin J (2015) Global cancer statistics. 2012. CA 65:87–108. https://doi.org/10.3322/caac.21262

    Article  Google Scholar 

  2. Ido W, Siegal S, Raphael C, Avraham K, Bella K (2005) Diabetes mellitus and breast cancer. Lancet Oncol 6:103–111. https://doi.org/10.1159/000152028

    Article  Google Scholar 

  3. Larsson SC, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 121:856–862. https://doi.org/10.1002/ijc.22717

    Article  CAS  PubMed  Google Scholar 

  4. Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, Fairley LL, Boniol M, Zheng T, Zhang Y, Pasterk M, Smans M, Curado MP, Mullie P, Gandini S, Bota M, Bolli GB, Rosenstock J, Autier P (2012) Diabetes and breast cancer risk: a meta-analysis. Brit J Cancer 107:1608–1617. https://doi.org/10.1038/bjc.2012.414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhao XB, Ren G (2016) Diabetes mellitus and prognosis in women with breast cancer. Medicine 95(49): https://doi.org/10.1097/md.0000000000005602

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schrauder MG, Fasching PA, Häberle L, Lux MP, Rauh C, Hein A, Bayer CM, Heusinger K, Hartmann A, Strehl JD, Wachter DL, Schulz-Wendtland R, Adamietz B, Beckmann MW, Loehberg CR (2011) Diabetes and prognosis in a breast cancer cohort. J Cancer Res Clin Oncol 137:975–983. https://doi.org/10.1007/s00432-010-0960-2

    Article  PubMed  Google Scholar 

  7. Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, Laughlin GA, Saquib N, Rock Cl L, Pierce JP (2011) Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol 29(1):54–60. https://doi.org/10.1200/JCO.2010.29.3183

    Article  PubMed  Google Scholar 

  8. Hardefeldt PJ, Edirimanne S, Eslick GD (2012) Diabetes increases the risk of breast cancer: a meta-analysis. Endocrine-Relat Cancer 19:793–803. https://doi.org/10.1530/erc-12-0242

    Article  Google Scholar 

  9. Candyce HK, Wendy YC, Bernard R, Michelle DH (2016) Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23:1370–1378. https://doi.org/10.1200/jco.2005.01.079

    Article  Google Scholar 

  10. Blonde L, Russell-Jones D (2009) The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1–5 studies Diabetes. Obes Metab 24:26–34. https://doi.org/10.1111/j.1463-1326.2009.01075.x

    Article  CAS  Google Scholar 

  11. Seino Y, Yabe D (2013) Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. J Diabet Invest 4(2):108–130. https://doi.org/10.1111/jdi.12065

    Article  CAS  Google Scholar 

  12. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DCW, Le-Roux CW, Violante OR, Jensen CB, Wilding JPH (2015) A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 373:11–22. https://doi.org/10.1056/nejmoa1411892

    Article  PubMed  Google Scholar 

  13. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC (2011) Pancreatitis, pancreatic, and thyroid cancer with Glucagon-like peptide-1based therapies. Gastroenterology 141:150–156. https://doi.org/10.1053/j.gastro.2011.02.018

    Article  CAS  PubMed  Google Scholar 

  14. Koehler JA, Baggio LL, Yusta B, Longuet C, Rowland KJ, Cao X, Holland D, Brubaker PL, Drucker DJ (2015) GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7. Cell Metab 21:379–391. https://doi.org/10.1016/j.cmet.2015.02.005

    Article  CAS  PubMed  Google Scholar 

  15. Hicks BM, Yin H, Yu OHY, Pollak MN, Platt RW, Azoulay L (2016) Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ 355:1–8. https://doi.org/10.1136/bmj.i5340

    Article  Google Scholar 

  16. Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N (2020) Japanese clinical practice guideline for diabetes 2019. Diabetol Int 11:165–223. https://doi.org/10.1007/s13340-020-00439-5

    Article  PubMed  PubMed Central  Google Scholar 

  17. Allison K, Hammond M, Hayes D, Dowsett M, Mckernin S, Carey L, Fitzgibbons P, Hayes D, Lakhani S, Chaves-MacGregor M, Perlmutter J, Perou C, Regan M, Rimm D, Symmans W, Torlakovic E, Varella L, Viale G, Weisberg T, McShane L, Wolff A (2020) Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol 38(12):1346–1366. https://doi.org/10.1200/JCO.19.02309

    Article  PubMed  Google Scholar 

  18. Song Y, Zhou M, Cao Y, Qi J, Geng J, Liu X (2017) Expression of GLP-1 receptor and CD26 in human thyroid C-cells: The association of thyroid C-cell tumorigenesis with incretin-based medicine. Oncol Lett 13:2684–2690. https://doi.org/10.3892/ol.2017.5752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sun S, Jiang Y, Zhang G, Song H, Zhang X, Zhang Y, Liang X, Sun Q, Pang D (2012) Increased expression of fibroblastic growth factor receptor 2 is correlated with poor prognosis in patients with breast cancer. J Surg Oncol 105:773–779. https://doi.org/10.1002/jso.22120

    Article  CAS  PubMed  Google Scholar 

  20. Fan EW, Li C-C, Wu W-J, Huang C-N, Li W-M, Ke H-L, Yeh H-C, Wu T-F, Liang P-I, Ma L-J, Li C-F (2015) FGF7 Over Expression is an Independent Prognosticator in Patients with Urothelial Carcinoma of the Upper Urinary Tract and Bladder. J Urol 194:223–229. https://doi.org/10.1016/j.juro.2015.01.073

    Article  CAS  PubMed  Google Scholar 

  21. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ (2011) Strategies for subtypes-dealing with the diversity of breast cancer: Highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 22:1736–1747. https://doi.org/10.1093/annonc/mdr304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ahrén B, Schmitz O (2004) GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. Horm Metab Res 36(11–12):867–876. https://doi.org/10.1055/s-2004-826178

    Article  CAS  PubMed  Google Scholar 

  23. Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T, Knop FK (2013) Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: Systematic review and meta-analyses of clinical studies. Diabetologia 56(5):965–972. https://doi.org/10.1007/s00125-013-2841-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamaoka TM, Tojo T, Takahira N, Matsunaga A, Aoyama N, Masuda T, Izumi T (2010) Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease. Cardiovasc Diabetol 9:1–9. https://doi.org/10.1186/1475-2840-9-17

    Article  CAS  Google Scholar 

  25. Kanda R, Hiraike H, Wada-Hiraike O, Ichinose T, Nagasaka K, Sasajima Y, Ryo E, Fujii T, Osuga Y, Ayabe T (2018) Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer. BMC Cancer 18(1):657. https://doi.org/10.1186/s12885-018-4570-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A, Kaufman B, Rubinek T (2012) The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat 132(2):449–461. https://doi.org/10.1007/s10549-011-1585-0

    Article  CAS  PubMed  Google Scholar 

  27. Pyke C, Heller RS, Kirk RK, Ørskov C, Reedtz-RS Kaastrup P, Hvelplund A, Bardram L, Calatayud D, Knudsen LB (2014) GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155(4):1280–1290. https://doi.org/10.1210/en.2013-1934

    Article  CAS  PubMed  Google Scholar 

  28. Seino Y, Yabe D (2011) Two incretin hormones GLP-1 and GIP: Comparison of their actions in insulin secretion and β cell preservation. Progress Biophys Mol Biol 107:248–256. https://doi.org/10.1016/j.pbiomolbio.2011.07.010

    Article  CAS  Google Scholar 

  29. Palmieri C, Roberts-Clark D, Assadi-Sabet A, Coope RC, O’Hare M, Sunters A, Hanby A, Slade MJ, Gomm JJ, Lam EWF, Coombes RC (2003) Fibroblast growth factor 7, secreted by breast fibroblasts, is an interleukin-1 -induced paracrine growth factor for human breast cells. J Endocrinol 77:65–81. https://doi.org/10.1677/joe.0.1770065

    Article  Google Scholar 

  30. Tannheimer SL, Rehemtulla A, Ethier SP (2000) Characterization of fibroblast growth factor receptor 2 overexpression in the human breast cancer cell line SUM-52PE. Breast Cancer Res 2:311–320. https://doi.org/10.1186/bcr73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lei H, Deng CX (2017) Fibroblast growth factor receptor 2 Signaling in Breast Cancer Haipeng Lei and Chu-Xia Deng. Int J Biol Sci 13(9):1163–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim S, Dubrovska A, Salamone RJ, Walker JR, Grandinetti KB, Bonamy GM, Orth AP, Elliott J, Porta DG, Garcia-Echeverria C, Reddy VA (2013) FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells. PLoS ONE 8(1):e51671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cui F, Wu D, Wang W, He X, Wang M (2016) Variants of FGFR2 and their associations with breast cancer risk: a HUGE systematic review and meta-analysis. Breast Cancer Res Treat 155:313–335. https://doi.org/10.1007/s10549-015-3670-2

    Article  CAS  PubMed  Google Scholar 

  34. Zang XP, Pento JT (2000) Keratinocyte growth factor-induced motility of breast cancer cells. Clin Exp Metastasis 18(7):573–580. https://doi.org/10.1023/A:1011997317994

    Article  CAS  PubMed  Google Scholar 

  35. Wu XY, Xu H, Wu ZF, Chen C, Liu JY, Wu GN, Yao XQ, Liu FK, Li G, Shen L (2015) Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models. Oncotarget 6(42):44563–44578. https://doi.org/10.18632/oncotarget.6310

    Article  PubMed  PubMed Central  Google Scholar 

  36. Eiro N, Cid S, Fraile M, Cabrera JR, Gonzalez LO, Vizoso FJ (2020) Analysis of the gene expression profile of stromal pro-tumor factors in cancer-associated fibroblasts from luminal breast carcinomas. Diagnostics (Basel) 10(11):865. https://doi.org/10.1023/a:1011997317994

    Article  CAS  Google Scholar 

  37. Cichon M, Degnim A, Visscher D, Radisky D (2010) Microenvironmental Influences that Drive Progression from Benign Breast Disease to Invasive Breast Cancer. J Mammary Gland Biol Neoplasia 15:389–397. https://doi.org/10.1007/s10911-010-9195-8

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hu M, Yao J, Carroll D, Weremowicz S, Chen H, Carrasco D, Richardson A, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein E, Hahn W, Gelman R, Allred C, Bissell M, Schnitt S, Polyak K (2008) Regulation of In Situ to Invasive Breast Carcinoma Transition. Cancer Cell 13(5):394–406. https://doi.org/10.1016/j.ccr.2008.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Manson JE (2003) Type 2 diabetes and subsequent incidence of breast cancer in the nurses’ health study. Diabetes Care 26:1752–1758. https://doi.org/10.2337/diacare.26.6.1752

    Article  PubMed  Google Scholar 

  40. Turczyk L, Kitowska K, Mieszkowska M, Mieczkowski K, Czaplinska D, Piasecka D, Kordek R, Skladanowski AC, Potemski P, Romanska HM, Sadej R (2017) FGFR2-driven signaling counteracts tamoxifen effect on ERα-positive breast cancer cells. Neoplasia 19:791–804. https://doi.org/10.1016/j.neo.2017.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study did not receive any financial support.

Author information

Authors and Affiliations

  1. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Naoko Hashimoto Takigami, Shimpei Kuniyoshi, Yasuhiro Miki, Kentaro Tamaki, Erina Iwabuchi, Ayako Kanai & Hironobu Sasano

  2. Department of Breast Surgical Oncology, Nahanishi Clinic, Naha, Okinawa, Japan

    Naoko Hashimoto Takigami, Kentaro Tamaki, Yoshihiko Kamada, Kano Uehara, Seiko Tsuchiya, Shigeharu Terukina & Nobumitsu Tamaki

  3. Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan

    Shimpei Kuniyoshi & Hironobu Sasano

  4. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Ayako Kanai, Minoru Miyashita & Takanori Ishida

Authors
  1. Naoko Hashimoto Takigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shimpei Kuniyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuhiro Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kentaro Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshihiko Kamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kano Uehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seiko Tsuchiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeharu Terukina
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Erina Iwabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ayako Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Minoru Miyashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takanori Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nobumitsu Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hironobu Sasano
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NHT and HS devised the project and the main conceptual ideas. NHT worked out almost all of the experiments and performed the analysis. SK and KT supervised the evaluation of immunohistochemistry. EI, YM, SK, KT interpreted the pathological results. SK and HS supervised the pathological examinations. NT and TI managed and provided the clinical data. YK, KU, SeT, ShT, NT, AK, and MM collected clinical data, selected appropriate cases, and evaluated the results. NT, TI, and HS interpreted and supervised the all results. NHT wrote the draft manuscript. YM, TK, NT, and HS reviewed and edited the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Hironobu Sasano.

Ethics declarations

Conflicts of interest

There are no conflicts of interest that needs to be disclosed.

Consent to participate

Informed consent was obtained from all participants.

Consent for publication

It was included in the approval of the Tohoku University Ethics Committee.

Ethical approval

Research protocols of this study were approved by the Ethical Committee of Tohoku University School of Medicine (no.2018-1-433) and Nahanishi Clinic (no. NNCEC2017007) Japan.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashimoto Takigami, N., Kuniyoshi, S., Miki, Y. et al. Breast Cancer, Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor Toward Exploring Their Possible Associations. Breast Cancer Res Treat 189, 39–48 (2021). https://doi.org/10.1007/s10549-021-06288-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-021-06288-3

Keywords

Search

Navigation