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:

Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes

Journal of Human Genetics volume 66, pages 519–534 (2021)Cite this article

Subjects

Abstract

Our recent research has revealed that passenger strands of certain microRNAs (miRNAs) function as tumor-suppressive miRNAs in cancer cells, e.g., miR-101-5p, miR-143-5p, miR-144-5p, miR-145-3p, and miR-150-3p. Thus, they are important in cancer pathogenesis. Analysis of the miRNA expression signature of breast cancer (BrCa) showed that the expression levels of two miRNAs derived from pre-miR-99a (miR-99a-5p and miR-99a-3p) were suppressed in cancerous tissues. The aim of this study was to identify oncogenic genes controlled by pre-miR-99a that are closely involved in the molecular pathogenesis of BrCa. A total of 113 genes were identified as targets of pre-miR-99a regulation (19 genes modulated by miR-99a-5p, and 95 genes regulated by miR-99a-3p) in BrCa cells. Notably, FAM64A was targeted by both of the miRNAs. Among these targets, high expression of 16 genes (C5orf22, YOD1, SLBP, F11R, C12orf49, SRPK1, ZNF250, ZNF695, CDK1, DNMT3B, TRIM25, MCM4, CDKN3, PRPS, FAM64A, and DESI2) significantly predicted reduced survival of BrCa patients based upon The Cancer Genome Atlas (TCGA) database. In this study, we focused on FAM64A and investigated the relationship between FAM64A expression and molecular pathogenesis of BrCa subtypes. The upregulation of FAM64A was confirmed in BrCa clinical specimens. Importantly, the expression of FAM64A significantly differed between patients with Luminal-A and Luminal-B subtypes. Our data strongly suggest that the aberrant expression of FAM64A is involved in the malignant transformation of BrCa. Our miRNA-based approaches (identification of tumor-suppressive miRNAs and their controlled targets) will provide novel information regarding the molecular pathogenesis of BrCa.

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

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    PubMed  Google Scholar 

  2. Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41:1–8.

    CAS  PubMed  Google Scholar 

  3. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110–20.

    CAS  PubMed  Google Scholar 

  4. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402–16.

    CAS  PubMed  Google Scholar 

  5. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    CAS  PubMed  Google Scholar 

  6. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. and Panel Members. 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. Ann Oncol. 2011;22:1736–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim. 2019;5:66.

    PubMed  Google Scholar 

  8. Rakha EA, Fresia GP. New advances in molecular breast cancer pathology. Semin Cancer Biol. 2020;S1044-579X:30080–8.

    Google Scholar 

  9. Jennifer JG, Sandra MS. Luminal a breast cancer and molecular assays: a review. Oncologist. 2018;23:556–65.

    Google Scholar 

  10. Anfossi S, Babayan A, Pantel K, Calin GA. Clinical utility of circulating non-coding RNAs—an update. Nat Rev Clin Oncol. 2018;15:541–63.

    PubMed  Google Scholar 

  11. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–24.

    CAS  PubMed  Google Scholar 

  12. Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019;20:21–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15:321–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.

    CAS  PubMed  Google Scholar 

  15. Toda H, Kurozumi S, Kijima Y, Idichi T, Shinden Y, Yamada Y, et al. Molecular pathogenesis of triple-negative breast cancer based on microRNA expression signatures: antitumor miR-204-5p targets AP1S3. J Hum Genet. 2018;63:1197–210.

    CAS  PubMed  Google Scholar 

  16. Toda H, Seki N, Kurozumi S, Shinden Y, Yamada Y, Nohata N, et al. RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis. Mol Oncol. 2020;14:426–46.

    CAS  PubMed  Google Scholar 

  17. Osako Y, Seki N, Koshizuka K, Okato A, Idichi T, Arai T, et al. Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma. J Hum Genet. 2017;62:935–44.

    CAS  PubMed  Google Scholar 

  18. Misono S, Seki N, Mizuno K, Yamada Y, Uchida A, Arai T, et al. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet. 2018;63:1015–28.

    CAS  PubMed  Google Scholar 

  19. Uchida A, Seki N, Mizuno K, Misono S, Yamada Y, Kikkawa N, et al. Involvement of dual-strand of the miR-144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma. Cancer Sci. 2019;110:420–32.

    CAS  PubMed  Google Scholar 

  20. Wada M, Goto Y, Tanaka T, Okada R, Moriya S, Idichi T, et al. RNA sequencing-based microRNA expression signature in esophageal squamous cell carcinoma: oncogenic targets by antitumor miR-143-5p and miR-143-3p regulation. J Hum Genet. 2020;65:1019–34.

    CAS  PubMed  Google Scholar 

  21. Mitra R, Adams CM, Jiang W, Greenawalt E, Eischen CM. Pan-cancer analysis reveals cooperativity of bothstrands of microRNA that regulate tumorigenesis and patient survival. Nat Commun. 2020;11:968.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Google Scholar 

  23. Pereira B, Chin S, Rueda OM, Moen VH, Provenzano E, Bardwell HA, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  25. Jiang L, Ren L, Zhang X, Chen H, Chen X, Lin C, et al. Overexpression of PIMREG promotes breast cancer aggressiveness via constitutive activation of NF-κB signaling. EBioMedicine. 2019;43:188–200.

    PubMed  PubMed Central  Google Scholar 

  26. Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget. 2017;8:70097–115.

    PubMed  PubMed Central  Google Scholar 

  27. Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget. 2017;8:30288–304.

    PubMed  PubMed Central  Google Scholar 

  28. Hu Y, Zhu Q, Tang L. MiR-99a antitumor activity in human breast cancer cells through targeting of mTOR expression. PLoS ONE. 2014;9:e92099.

    PubMed  PubMed Central  Google Scholar 

  29. Yang Z, Han Y, Cheng K, Zhang G, Wang X. miR-99a directly targets the mTOR signalling pathway in breast cancer side population cells. Cell Prolif. 2014;47:587–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang X, Li Y, Qi W, Zhang N, Sun M, Huo Q, et al. MicroRNA-99a inhibits tumor aggressive phenotypes through regulating HOXA1 in breast cancer cells. Oncotarget. 2015;6:32737–47.

    PubMed  PubMed Central  Google Scholar 

  31. Xia M, Li H, Wang JJ, Zeng HJ, Wang SH. MiR-99a suppress proliferation, migration and invasion through regulating insulin-like growth factor 1 receptor in breast cancer. Eur Rev Med Pharmacol Sci. 2016;20:1755–63.

    CAS  PubMed  Google Scholar 

  32. Qin H, Liu W. MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. J Cell Physiol. 2019;234:3526–37.

    CAS  PubMed  Google Scholar 

  33. Long X, Shi Y, Ye P, Guo J, Zhou Q, Tang Y, et al. MicroRNA-99a suppresses breast cancer progression by targeting FGFR3. Front Oncol. 2020;9:1473.

    PubMed  PubMed Central  Google Scholar 

  34. Osako Y, Yoshino H, Sakaguchi T, Sugita S, Yonemori M, Nakagawa M, et al. Potential tumor-suppressive role of microRNA-99a-3p in sunitinib-resistant renal cell carcinoma cells through the regulation of RRM2. Int J Oncol. 2019;54:1759–70.

    CAS  PubMed  Google Scholar 

  35. Arai T, Okato A, Yamada Y, Sugawara S, Kurozumi A, Kojima S, et al. Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC. Cancer Med. 2018;7:1988–2002.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Okada R, Koshizuka K, Yamada Y, Moriya S, Kikkawa N, Kinoshita T, et al. Regulation of oncogenic targets by miR-99a-3p (passenger strand of miR-99a-duplex) in head and neck squamous cell carcinoma. Cells. 2019;8:1535.

    CAS  PubMed Central  Google Scholar 

  37. Leech AO, Vellanki SH, Rutherford EJ, Keogh A, Jahns H, Hudson L, et al. Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings. Breast Cancer Res. 2018;20:140.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. So JY, Skrypek N, Yang HH, Merchant AS, Nelson GW, Chen WD, et al. Induction of DNMT3B by PGE2 and IL6 at distant metastatic sites promotes epigenetic modification and breast cancer colonization. Cancer Res. 2020;80:2612–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Walsh LA, Alvarez MJ, Sabio EY, Reyngold M, Makarov V, Mukherjee S, et al. An integrated systems biology approach identifies TRIM25 as a key determinant of breast cancer metastasis. Cell Rep. 2017;20:1623–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Archangelo LF, Gläsner J, Krause A, Bohlander SK. The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10. Oncogene. 2006;25:4099–109.

    CAS  PubMed  Google Scholar 

  41. Archangelo LF, Greif PA, Hölzel M, Harasim T, Kremmer E, Przemeck GK, et al. The CALM and CALM/AF10 interactor CATS is a marker for proliferation. Mol Oncol. 2008;2:356–67.

    PubMed  PubMed Central  Google Scholar 

  42. Caudell D, Aplan PD. The role of CALM-AF10 gene fusion in acute leukemia. Leukemia. 2008;22:678–85.

    CAS  PubMed  Google Scholar 

  43. Hu S, Yuan H, Li Z, Zhang J, Wu J, Chen Y, et al. Transcriptional response profiles of paired tumor-normal samples offer novel perspectives in pan-cancer analysis. Oncotarget. 2017;8:41334–47.

    PubMed  PubMed Central  Google Scholar 

  44. Yao Z, Zheng X, Lu S, He Z, Miao Y, Huang H, et al. Knockdown of FAM64A suppresses proliferation and migration of breast cancer cells. Breast Cancer. 2019;26:835–45.

    PubMed  Google Scholar 

  45. Zhang J, Qian L, Wu J, Lu D, Yuan H, Li W, et al. Up-regulation of FAM64A promotes epithelial-to-mesenchymal transition and enhances stemness features in breast cancer cells. Biochem Biophys Res Commun. 2019;513:472–8.

    CAS  PubMed  Google Scholar 

  46. Ignatiadis M, Sotiriou C. Luminal breast cancer: from biology to treatment. Nat Rev Clin Oncol. 2013;10:494–506.

    CAS  PubMed  Google Scholar 

  47. Gao JJ, Swain SM. Luminal A breast cancer and molecular assays: a review. Oncologist. 2018;23:556–65.

    PubMed  PubMed Central  Google Scholar 

  48. Kyrochristos ID, Ziogas DE, Roukos DH. Dynamic genome and transcriptional network-based biomarkers and drugs: precision in breast cancer therapy. Med Res Rev. 2019;39:1205–27.

    CAS  PubMed  Google Scholar 

  49. Araki K, Miyoshi Y. Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer. 2018;25:392–401.

    PubMed  Google Scholar 

  50. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–30.

    PubMed  Google Scholar 

  51. Sobhani N, D’Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, et al. Updates on the CDK4/6 inhibitory strategy and combinations in breast. Cancer Cells. 2019;8:321.

    CAS  Google Scholar 

  52. Pandey K, An HJ, Kim SK, Lee SA, Kim S, Lim SM, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer. 2019;145:1179–88.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The present study was supported by KAKENHI grants 18K09338, 19K09049, and 19K18060.

Author information

Author notes

  1. These authors contributed equally: Yoshiaki Shinden, Tadahiro Hirashima

Authors and Affiliations

  1. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Yoshiaki Shinden, Tadahiro Hirashima, Takako Tanaka, Yuto Hozaka & Takao Ohtsuka

  2. MSD K.K., Tokyo, Japan

    Nijiro Nohata

  3. Department of Breast Surgery, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan

    Hiroko Toda & Yuko Kijima

  4. Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan

    Reona Okada, Shunichi Asai & Naohiko Seki

Authors
  1. Yoshiaki Shinden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadahiro Hirashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nijiro Nohata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroko Toda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reona Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shunichi Asai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takako Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuto Hozaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takao Ohtsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuko Kijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Naohiko Seki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naohiko Seki.

Ethics declarations

Conflict of interest

NN is an employee of MSD K.K., a subsidiary of Merck & Co., Inc. and reports personal fees from MSD K.K. outside this study. The authors declare no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shinden, Y., Hirashima, T., Nohata, N. et al. Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes. J Hum Genet 66, 519–534 (2021). https://doi.org/10.1038/s10038-020-00865-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-020-00865-y

Search

Advanced search

Quick links