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İnvaziv Meme Karsinomunda Cyclin D1 Aşırı Ekspresyonunun Prognostik Değeri

Year 2025, Volume: 4 Issue: 1, 23 - 33

Abstract

Amaç: Meme kanseri, dünya genelinde en sık tanı konulan kanser olup tüm kanserlerin %11,7’sini oluşturmaktadır. Cyclin D1, CDK4/6 ve hücre döngüsü ilerlemesini düzenleyen bir onkogen olarak aşırı ekspresyon yoluyla meme karsinomu da dahil olmak üzere çeşitli kanserlerin patogenezine katkıda bulunmaktadır. Bu çalışmada, Türk popülasyonunda invaziv meme karsinomunda Cyclin D1 ekspresyonu ve klinikopatolojik önemi değerlendirildi.
Yöntemler: 2007-2013 yılları arasında tanı konulan 143 hastaya ait parsiyel ve total mastektomi örneklerinden hazırlanan H&E ve immünohistokimyasal preparatlar incelendi. Cyclin D1 aşırı ekspresyonu, nükleer boyanma şiddetine (0-3) ve pozitif tümör hücrelerinin yüzdesine (1-3) dayalı IHC skoru kullanılarak 1000 hücrede değerlendirildi. Bulgular zayıf pozitif ('+' veya '++') veya güçlü pozitif ('+++') olarak sınıflandırıldı. Cyclin D1 ekspresyonu ile klinikopatolojik parametreler arasındaki ilişki, Pearson Ki-Kare ve Spearman rho testi kullanılarak analiz edildi.
Bulgular: Hastaların medyan yaşı 58,5 yıl (Min: 28, Maks: 92) idi. Cyclin D1 durumu ile yaş, T evresi veya lenf nodu metastazı arasında anlamlı bir ilişki bulunmadı. Ancak, ER (r = 0,32, P < ,001) ve PR (r = 0,31, P <, 001) skorlarıyla orta derecede pozitif bir korelasyon gözlendi. Moleküler alt gruplar içinde, Cyclin D1 aşırı ekspresyonu en çok Luminal B grubunda (%92,9, P = ,008) saptandı ve Triple negatif grupta anlamlı derecede düşük ekspresyon (%40, P = ,008) gözlendi.
Sonuç: Cyclin D1'in Luminal A ve Luminal B gruplarında aşırı ekspresyonu ve ER ile pozitif korelasyonu, bu proteinin östrojen duyarlı meme kanseri patogenezindeki rolünü düşündürmektedir. HER2-pozitif olgularda güçlü Cyclin D1 aşırı ekspresyonu, azalmış sağkalım süresi ile ilişkili bulunmuştur.

References

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  • 4. Roy M, Fowler AM, Ulaner GA, Mahajan A. Molecular Classification of Breast Cancer. PET Clin. 2023;18(4):441-458. doi:10.1016/j.cpet.2023.04.002
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  • 6. Deshpande A, Sicinski P, Hinds PW. Cyclins and cdks in development and cancer: A perspective. Oncogene. 2005;24(17):2909-2915. doi:10.1038/sj.onc.1208618
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  • 9. Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists guideline update. Arch Pathol Lab Med. 2020;144(5):545-563. doi:10.5858/arpa.2019-0904-SA
  • 10. Wolff AC, McShane LM, Hammond MEH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11). doi:10.5858/arpa.2018-0902-SA
  • 11. Bouzidi L, Makni S, Feki J, et al. Immunohistochemical Overexpression of Cyclin D1 in Tunisian Invasive Breast Carcinoma Women. Arch Iran Med. 2022;25(4):250-256. doi:10.34172/aim.2022.41
  • 12. Mylona E, Tzelepis K, Theohari I, Giannopoulou I, Papadimitriou C, Nakopoulou L. Cyclin D1 in invasive breast carcinoma: Favourable prognostic significance in unselected patients and within subgroups with an aggressive phenotype. Histopathology. 2013;62(3):472-480. doi:10.1111/his.12013
  • 13. Ahlin C, Lundgren C, Embretsén-Varro E, Jirström K, Blomqvist C, Fjällskog ML. High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers. Breast Cancer Res Treat. 2017;164(3):667-678. doi:10.1007/s10549-017-4294-5
  • 14. Guo LL, Gao P, Wu YG, et al. Alteration of Cyclin D1 in Chinese Patients with Breast Carcinoma and its Correlation with Ki-67, pRb, and p53. Arch Med Res. 2007;38(8):846-852. doi:10.1016/j.arcmed.2007.06.004
  • 15. He Y, Liu Z, Qiao C, Xu M, Yu J, Li G. Expression and significance of Wnt signaling components and their target genes in breast carcinoma. Mol Med Rep. 2014;9(1):137-143. doi:10.3892/mmr.2013.1774
  • 16. Montalto FI, De Amicis F. Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells. 2020;9(12):2648. doi:10.3390/cells9122648
  • 17. Ravikumar G, Ananthamurthy A. Cyclin D1 expression in ductal carcinoma of the breast and its correlation with other prognostic parameters. J Cancer Res Ther. 2014;10(3):671-675. doi:10.4103/0973-1482.138135
  • 18. Yang C, Chen L, Li C, Lynch MC, Brisken C, Schmidt E V. Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression. Mol Cell Biol. 2010;30(12):3111-3125. doi:10.1128/MCB.01398-09
  • 19. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi:10.1038/nature11412.
  • 20. Holah NS, Hemida AS. Cyclin D1 and PSA act as good prognostic and clinicopathological indicators for breast cancer. J Immunoassay Immunochem. 2020;41(1):28-44. doi:10.1080/15321819.2019.1677706
  • 21. Cheng CW, Liu YF, Yu JC, et al. Prognostic significance of cyclin D1, b-catenin, and MTA1 in patients with invasive ductal carcinoma of the breast. Ann Surg Oncol. 2012;19(13):4129-4139. doi:10.1245/s10434-012-2541-x
  • 22. An HX, He Q, Wu J, et al. Clinicopathological and prognostic significance of cyclin D1 amplification in patients with breast cancer: a meta-analysis. JBUON. 2017;22(5):1209-1216.
  • 23. Moradi Binabaj M, Bahrami A, Khazaei M, et al. The prognostic value of cyclin D1 expression in the survival of cancer patients: A meta-analysis. Gene. 2020;728:144283. doi:10.1016/j.gene.2019.144283
  • 24. Lee A, Park WC, Yim HW, Lee MA, Park G, Lee KY. Expression of c-erbB2, cyclin D1 and estrogen receptor and their clinical implications in the invasive ductal carcinoma of the breast. Jpn J Clin Oncol. 2007;37(9):708-714. doi:10.1093/jjco/hym082
  • 25. Bostner J, Ahnström Waltersson M, Fornander T, Skoog L, Nordenskjöld B, Stål O. Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene. 2007;26(49):6997-7005. doi:10.1038/sj.onc.1210506
  • 26. Beca F, Pereira M, Cameselle-Teijeiro JF, Martins D, Schmitt F. Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer. BMC Cancer. 2015;15:285. doi:10.1186/s12885-015-1266-1.
  • 27. Tobin NP, Lundgren KL, Conway C, Anagnostaki L, Costello S, Landberg G. Automated image analysis of cyclin D1 protein expression in invasive lobular breast carcinoma provides independent prognostic information. Hum Pathol. 2012;43(11). doi:10.1016/j.humpath.2012.02.015
  • 28. Aaltonen K, Amini RM, Landberg G, Eerola H. Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2008;113(1):75-82.
  • 29. Umekita Y, Ohi Y, Sagara Y, Yoshida H. Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor-negative breast cancer patients. Int J Cancer. 2002;98(3):415-418. doi:10.1002/ijc.10151
  • 30. Goel S, Wang Q, Watt AC, et al. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016;29(3):255-269. doi:10.1016/j.ccell.2016.02.006
  • 31. Choi C, Park S, Cho WK, Choi DH. Cyclin D1 is associated with radiosensitivity of triple-negative breast cancer cells to proton beam irradiation. Int J Mol Sci. 2019;20(19):4943. doi:10.3390/ijms20194943
  • 32. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol. 2018;10:1758835918786451. doi:10.1177/1758835918786451.
  • 33. De Amicis F, Chiodo C, Morelli C, et al. AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells. BMC Cancer. 2019;19(1):1038. doi:10.1186/s12885-019-6262-4.
  • 34. Yu Z, Wang C, Wang M, et al. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol. 2008;182(3):509-517. doi:10.1083/jcb.200801079.
  • 35. Lu J, Zhao Q, Ding X, et al. Cyclin D1 promotes secretion of pro-oncogenic immuno-miRNAs and piRNAs. Clin Sci. 2020;134(7): 791-805. doi:10.1042/CS20191318

Prognostic Value of Cyclin D1 Overexpression in Invasive Breast Carcinoma

Year 2025, Volume: 4 Issue: 1, 23 - 33

Abstract

Objective: Breast cancer is the most diagnosed cancer worldwide, accounting for 11.7% of all cancers. Cyclin D1, a regulator of CDK4/6 and cell cycle progression, functions as an oncogene through overexpression, contributing to the pathogenesis of cancers including breast carcinoma. This study aimed to evaluate Cyclin D1 expression and its clinicopathological significance in invasive breast carcinoma within the Turkish population.
Methods: H&E-stained and immunohistochemical preparations from partial and total mastectomy specimens of 143 patients, diagnosed between 2007 and 2013, were examined. Cyclin D1 overexpression was evaluated in 1000 cells using an IHC score based on nuclear staining intensity (0-3) and the percentage of positive tumor cells (1-3), classified as weak ('+' or '++') or strong positive ('+++'). Pearson's Chi-Square and Spearman's rho were used to analyze the relationship between Cyclin D1 expression and clinicopathological parameters statistically.
Results: The median age of the patients was 58.5 years (Min:28, Max:92). Cyclin D1 status showed no correlation with age, T stage, or lymph node metastasis. However, a moderate positive correlation was observed with ER (r = 0.32, P <.001) and PR (r = 0.31, P <.001) scores. Among molecular subgroups, Cyclin D1 overexpression was most significant in Luminal B group (92.9%, P = .008), while Triple-negative group showed significantly lower overexpression (40%, P = .008).
Conclusion: Cyclin D1 overexpression in Luminal B and Luminal A groups, along with its positive correlation with ER, suggests its role in estrogen-sensitive breast cancer pathogenesis. Strong Cyclin D1 overexpression was associated with reduced survival time in HER2-positive cases.

Ethical Statement

Ethical approval for the study was obtained from the İzmir Bozyaka Education and Research Hospital Ethics Committee on June 7, 2016 (Decision No. 4).

References

  • 1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
  • 2. T.C. Saglik Bakanligi Halk Sagligi Genel Mudurlugu. Turkiye Kanser Istatistikleri 2018. Ankara: T.C. Saglik Bakanligi; 2022.
  • 3. Tan PH, Ellis I, Allison K, et al. The 2019 World Health Organization classification of tumours of the breast. Histopathology.2020;77(2):181-185. doi:10.1111/his.14091
  • 4. Roy M, Fowler AM, Ulaner GA, Mahajan A. Molecular Classification of Breast Cancer. PET Clin. 2023;18(4):441-458. doi:10.1016/j.cpet.2023.04.002
  • 5. Tchakarska G, Sola B. The double dealing of cyclin D1. Cell Cycle. 2020;19(2):163-178. doi:10.1080/15384101.2019.1706903
  • 6. Deshpande A, Sicinski P, Hinds PW. Cyclins and cdks in development and cancer: A perspective. Oncogene. 2005;24(17):2909-2915. doi:10.1038/sj.onc.1208618
  • 7. Dwyer M. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. NCCN.org. Published 2023. Available at: https://www.nccn.org.
  • 8. Guo L, Liu S, Jakulin A, Yilamu D, Wang B, Yan J. Positive expression of cyclin D1 is an indicator for the evaluation of the prognosis of breast cancer. Int J Clin Exp Med. 2015;8(10):18656-18664.
  • 9. Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists guideline update. Arch Pathol Lab Med. 2020;144(5):545-563. doi:10.5858/arpa.2019-0904-SA
  • 10. Wolff AC, McShane LM, Hammond MEH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11). doi:10.5858/arpa.2018-0902-SA
  • 11. Bouzidi L, Makni S, Feki J, et al. Immunohistochemical Overexpression of Cyclin D1 in Tunisian Invasive Breast Carcinoma Women. Arch Iran Med. 2022;25(4):250-256. doi:10.34172/aim.2022.41
  • 12. Mylona E, Tzelepis K, Theohari I, Giannopoulou I, Papadimitriou C, Nakopoulou L. Cyclin D1 in invasive breast carcinoma: Favourable prognostic significance in unselected patients and within subgroups with an aggressive phenotype. Histopathology. 2013;62(3):472-480. doi:10.1111/his.12013
  • 13. Ahlin C, Lundgren C, Embretsén-Varro E, Jirström K, Blomqvist C, Fjällskog ML. High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers. Breast Cancer Res Treat. 2017;164(3):667-678. doi:10.1007/s10549-017-4294-5
  • 14. Guo LL, Gao P, Wu YG, et al. Alteration of Cyclin D1 in Chinese Patients with Breast Carcinoma and its Correlation with Ki-67, pRb, and p53. Arch Med Res. 2007;38(8):846-852. doi:10.1016/j.arcmed.2007.06.004
  • 15. He Y, Liu Z, Qiao C, Xu M, Yu J, Li G. Expression and significance of Wnt signaling components and their target genes in breast carcinoma. Mol Med Rep. 2014;9(1):137-143. doi:10.3892/mmr.2013.1774
  • 16. Montalto FI, De Amicis F. Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells. 2020;9(12):2648. doi:10.3390/cells9122648
  • 17. Ravikumar G, Ananthamurthy A. Cyclin D1 expression in ductal carcinoma of the breast and its correlation with other prognostic parameters. J Cancer Res Ther. 2014;10(3):671-675. doi:10.4103/0973-1482.138135
  • 18. Yang C, Chen L, Li C, Lynch MC, Brisken C, Schmidt E V. Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression. Mol Cell Biol. 2010;30(12):3111-3125. doi:10.1128/MCB.01398-09
  • 19. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. doi:10.1038/nature11412.
  • 20. Holah NS, Hemida AS. Cyclin D1 and PSA act as good prognostic and clinicopathological indicators for breast cancer. J Immunoassay Immunochem. 2020;41(1):28-44. doi:10.1080/15321819.2019.1677706
  • 21. Cheng CW, Liu YF, Yu JC, et al. Prognostic significance of cyclin D1, b-catenin, and MTA1 in patients with invasive ductal carcinoma of the breast. Ann Surg Oncol. 2012;19(13):4129-4139. doi:10.1245/s10434-012-2541-x
  • 22. An HX, He Q, Wu J, et al. Clinicopathological and prognostic significance of cyclin D1 amplification in patients with breast cancer: a meta-analysis. JBUON. 2017;22(5):1209-1216.
  • 23. Moradi Binabaj M, Bahrami A, Khazaei M, et al. The prognostic value of cyclin D1 expression in the survival of cancer patients: A meta-analysis. Gene. 2020;728:144283. doi:10.1016/j.gene.2019.144283
  • 24. Lee A, Park WC, Yim HW, Lee MA, Park G, Lee KY. Expression of c-erbB2, cyclin D1 and estrogen receptor and their clinical implications in the invasive ductal carcinoma of the breast. Jpn J Clin Oncol. 2007;37(9):708-714. doi:10.1093/jjco/hym082
  • 25. Bostner J, Ahnström Waltersson M, Fornander T, Skoog L, Nordenskjöld B, Stål O. Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene. 2007;26(49):6997-7005. doi:10.1038/sj.onc.1210506
  • 26. Beca F, Pereira M, Cameselle-Teijeiro JF, Martins D, Schmitt F. Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer. BMC Cancer. 2015;15:285. doi:10.1186/s12885-015-1266-1.
  • 27. Tobin NP, Lundgren KL, Conway C, Anagnostaki L, Costello S, Landberg G. Automated image analysis of cyclin D1 protein expression in invasive lobular breast carcinoma provides independent prognostic information. Hum Pathol. 2012;43(11). doi:10.1016/j.humpath.2012.02.015
  • 28. Aaltonen K, Amini RM, Landberg G, Eerola H. Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2008;113(1):75-82.
  • 29. Umekita Y, Ohi Y, Sagara Y, Yoshida H. Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor-negative breast cancer patients. Int J Cancer. 2002;98(3):415-418. doi:10.1002/ijc.10151
  • 30. Goel S, Wang Q, Watt AC, et al. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016;29(3):255-269. doi:10.1016/j.ccell.2016.02.006
  • 31. Choi C, Park S, Cho WK, Choi DH. Cyclin D1 is associated with radiosensitivity of triple-negative breast cancer cells to proton beam irradiation. Int J Mol Sci. 2019;20(19):4943. doi:10.3390/ijms20194943
  • 32. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol. 2018;10:1758835918786451. doi:10.1177/1758835918786451.
  • 33. De Amicis F, Chiodo C, Morelli C, et al. AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells. BMC Cancer. 2019;19(1):1038. doi:10.1186/s12885-019-6262-4.
  • 34. Yu Z, Wang C, Wang M, et al. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol. 2008;182(3):509-517. doi:10.1083/jcb.200801079.
  • 35. Lu J, Zhao Q, Ding X, et al. Cyclin D1 promotes secretion of pro-oncogenic immuno-miRNAs and piRNAs. Clin Sci. 2020;134(7): 791-805. doi:10.1042/CS20191318
There are 35 citations in total.

Details

Primary Language English
Subjects General Surgery
Journal Section Research Articles
Authors

Erdem Çomut 0000-0002-3386-4206

Demet Kocatepe Çavdar 0000-0002-3278-3770

Ayşe Yağcı 0009-0003-3658-6349

Enver Vardar 0000-0001-5371-4021

Funda Taşlı 0000-0001-5145-0026

Early Pub Date April 8, 2025
Publication Date
Submission Date January 29, 2025
Acceptance Date March 12, 2025
Published in Issue Year 2025 Volume: 4 Issue: 1

Cite

AMA Çomut E, Kocatepe Çavdar D, Yağcı A, Vardar E, Taşlı F. Prognostic Value of Cyclin D1 Overexpression in Invasive Breast Carcinoma. Trends in Surgical Sciences. April 2025;4(1):23-33.

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