Changes in mRNA expression of oncogenesis driver genes in atypical ductal breast hyperplasia

Background. Atypical ductal hyperplasia is a relatively common breast lesion that increases the risk of breast cancer by 3.5 to 5 times. Genomic rearrangements underlying the development of atypical proliferative lesions and breast cancer lead to gene expression changings.
Aim. To determine the mRNA expression profile of neoplasia and oncogenesis driver genes in atypical ductal hyperplasia of the breast.
Materials and methods. The real-time reverse transcription polymerase chain reaction was used to explore the expression profile of 46 genes in 107 samples of formalin-fixed paraffin-embedded (FFPE) specimens from atypical ductal hyperplasia, ductal hyperplasia without atypia, ductal carcinoma in situ and normal breast tissue.
Results. In atypical ductal hyperplasia, we detected changes in the expression of 22 of 46 studied genes, including ESR1, AR, PRLR, FGFR4, MKI67, CCNB1, KIF14, PAK1, MMP11, GATA3, FOXA1, ZNF703, which were upregulated, and MYC, which was downregulated.
Conclusion. The transcriptional signature of atypical ductal hyperplasia was similar to that of ductal carcinoma in situ and breast cancer of luminal subtypes.

1. Simpsons J. WHO Classification of Tumors of the Breast. Lyon: IARC Press 2012. Pp. 88, 89.

2. Rubin E., Visscher D.W., Alexander R.W. et al. Proliferative disease and atypia in biopsies performed for nonpalpable lesions detected mammographically. Cancer 1988;61:2077–82.

3. Liberman L., Cohen M.A., Dershaw D.D. et al. Atypical ductal hyperplasia diagnosed at stereotaxic core biopsy of breast lesions: an indication for surgical biopsy. AJR Am J Roentgenol 1995;164:1111–3.

4. Ioffe O.B., Berg W.A., Silverberg S.G., Kumar D. Mammographichistopathologic correlation of large-core needle biopsies of the breast. Mod Pathol 1998;11:721–7.

5. Friedenreich C., Bryant H., Alexander F. et al. Risk factors for benign proliferative breast disease. Int J Epidemiol 2000;29:637–44. DOI: 10.1093/ije/29.4.637

6. Dyrstad S.W., Yan Y., Fowler A.M., Colditz G.A. Breast cancer risk associated with benign breast disease: systematic review and metaanalysis. Breast Cancer Res Treat 2015;149:569–75. DOI: 10.1007/s10549-014-3254-6

7. Salamat F., Niakan B., Keshtkar A. et al. Subtypes of benign breast disease as a risk factor of breast cancer: A systematic review and meta analyses. Iran J Med Sci 2018;43(4):355–64.

8. Myers D.J., Walls A.L. Atypical Breast Hyperplasia. In: StatPearls. Treasure Island: StatPearls Publishing, 2023.

9. Burmenskaya O.V., Trofimov D.Yu., Kometova V.V. et al. Development and experience of using a transcriptional gene signature in the diagnosis of molecular subtypes of breast cancer. Akusherstvo i ginekologiya = Obstetrics and Gynecology 2020;(2):132–40. (In Russ.). DOI: 10.18565/aig.2020.2.132-140

10. Danforth D.N. Molecular profile of atypical hyperplasia of the breast. Breast Cancer Res Treat 2018;167(1):9–29. DOI: 10.1007/s10549-017-4488-x

11. O’Connell P., Pekkel V., Allred D.C. et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90(9):697–703.

12. Lakhani S., Collins N., Stratton M., Sloane J. Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol 1995;48(7):611–5.

13. Gao Y., Niu Y., Wang X. et al. Genetic changes at specific stages of breast cancer progression detected by comparative genomic hybridization. J Mol Med 2009;87(2):145–52. DOI: 10.1007/s00109-008-0408-1

14. Larson P.S., de las Morenas A., Cerda S.R. et al. Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors. J Pathol 2006;209(3):307–16. DOI: 10.1002/path.1973

15. Sahar A.D., Wesam M.I., Mohamed S.A. et al. Possible prognostic role of HER2/neu in ductal carcinoma in situ and atypical ductal proliferative lesions of the breast. Asian Pac J Cancer Prev 2016;17(8):3733–6.

16. Gregory K.J., Roberts A.L., Conlon E.M. et al. Gene expression signature of atypical breast hyperplasia and regulation by SFRP1. Breast Cancer Res 2019;21(1):76. DOI: 10.1186/s13058-019-1157-5

17. Brunner A.L., Li J., Guo X., Sweeney R.T. et al. A shared transcriptional program in early breast neoplasias despite genetic and clinical distinctions. Genome Biol 2014;15(5):1–16. DOI: 10.1186/gb-2014-15-5-r71

18. Clevenger C.V., Rui H. Breast cancer and prolactin – new mechanisms and models. Endocrinology 2022;163(10):bqac122. DOI: 10.1210/endocr/bqac122

19. Hammer A., Diakonova M. Tyrosyl phosphorylated serine-threonine kinase PAK1 is a novel regulator of prolactindependent breast cancer cell motility and invasion. Adv Exp Med Biol 2015;846:97–137. DOI: 10.1007/978-3-319-12114-7_5

20. Helsten T., Elkin S., Arthur E. et al. The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 2016;22:259–67. DOI: 10.1158/1078-0432.CCR-14-3212

21. Wesche J., Haglund K., Haugsten E.M. Fibroblast growth factors and their receptors in cancer. Biochem J 2011;437:199–213. DOI: 10.1042/BJ20101603