İnvaziv duktal karsinomlarda bcl 2 ve katepsin D’nin prognostik faktörlerle ilişkisi

GİRİŞ Meme kanserlerinden invaziv duktal karsinom, kadınlarda en sık görülen meme kanseridir. Bu tümörlerde erken tanı ve uygun tedavi yaşam süresini önemli ölçüde etkilemektedir. Bu nedenle son yıllardaki çalışmaların, meme kanserlerinde prognozu belirleme ve sistemik yayılımı önleme amacıyla hormonal ve kemoterapötik ajanlarla tedavide yoğunlaştığı görülmektedir. Sadece klasik parametrelerin prognozu ve tedaviyi yönlendirmede yeterli olmaması nedeniyle yeni, güvenilir belirleyicilere gerek vardır. Bu nedenle bu çalışmada, memenin invaziv duktal karsinom (İDK)’unda bcl-2 ve katepsin D’nin birbirleriyle ve diğer prognostik faktörlerle olan ilişkisi araştırıldı. GEREÇ VE YÖNTEM 2004-2006 yılları arasında Yüzüncü Yıl Üniversitesi Tıp Fakültesi Patoloji Ana Bilim Dalında mastektomi ve aksiller diseksiyon materyali incelenen ve invaziv duktal karsinom tanısı alan 50 adet olgu çalışmaya alındı. Bu olguların tümör diferansiyasyonu, histolojik derece ve nükleer skor (NS)’ları ile mitoz sayısı Bloom Richardson'a göre ayrı ayrı değerlendirildi. Bunun yanısıra tümör çevresi lenfatik, kan damarı ve perinöral invazyonun varlığı araştırıldı. Tümörün deri ile ilişkisi saptandı. Tümör çapı ve aksiller lenf nodlarının durumu değerlendirildi. Multifokal ve multisentrik tümörlerde, en büyük tümörün çapı ele alındı. Östrojen, progesteron ve c-erbB-2 ile boyanmış olan lamlar tekrar gözden geçirilerek her biri için ayrı ayrı skorlama yapıldı. Ayrıca 50 invaziv duktal karsinom olgusu, bcl-2 ve katepsin D ile immünhistokimyasal olarak boyandı ve her biri için ayrı ayrı skorlama yapılarak sonuçlar birbirleri ve diğer prognostik faktörlerle karşılaştırılarak değerlendirildi. BULGULAR Progesteron reseptörü ve düşük NS ile bcl-2 ekspresyonu arasında güçlü pozitif bir ilişki tespit edilirken katepsin D ve diğer prognostik faktörlerle bcl-2 ekspresyonu arasında güçlü pozitif bir ilişki tespit edilmedi. Perinöral invazyon, lenf damarı invazyonu, kan damarı invazyonu ve yüksek NS ile katepsin D ekspresyonu arasında güçlü pozitif bir ilişki gözlenirken diğer prognostik faktörler, c-erbB2, progesteron reseptörü, östrojen reseptörü ile katepsin D ekspresyonu arasında güçlü bir ilişki gözlenmedi. SONUÇ Bcl-2’nin düşük dereceli, katepsin D’nin ise yüksek dereceli ve invazyon yeteneği kazanmış invaziv duktal karsinom olgularının belirlenmesinde önemli olabileceği düşünülmektedir.

The correlation with prognostic factors of bcl-2 and cathepsin D in invasive ductal carcinomas

Introduction: Invasive ductal carcinoma which is cancers of the breast is the most common cancer of the breast in women. In this tumors, early diagnosis and appropriate medical treatment is to influence markedly to life span. For this reason, cancers of the breast is occured intesify at therapy with chemotherapotic agents and hormonal treatment for the purpose of prevention systemic spread and prognosis determination of works in the last years. Just reliable determinatives are necessary, because of not to be adequate to orientate treatment and prognosis only classıc parameters. For this reason, it was evaluated the correlation with each other and other prognostic factors of bcl-2 and cathepsin D in invasive ductal carcinomas of the breast in the present study.Materials and methods: In the present study. it was included 50 cases diagnosed with invasive ductal carcinoma and examined mastectomy and axillary dissection material. Slides stained  with estrogen, progesterone and c-erbB-2 were reviewed again and done scoring separately for each slide.Also in the present study it was stained bcl-2 and cathepsin D expression in 50 invasive ductal carcinomas by immünhistochemistry, and evaluated the correlation with other prognostic factors and each other.Results: A strong positive relationship was not detected between bcl-2 expression with other prognostic factors and cathepsin D protein, while a strong positive relationship was detected between bcl-2 expression with low nuclear grade and progesterone receptor’ status. A strong correlation was not observed between cathepsin D expression with oestrogen receptor’ status and progesterone receptor’ status and c-erbB-2 oncogene amplification and other prognostic factors, while a strong correlation was also observed between cathepsin D expression with high nuclear grade and blood vessel invasion and lymph-vessel invasion and perineural invasion. Conclusion: Bcl-2 is thought to be important in determining of invasive ductal carcinoma cases with low grade, while cathepsin D is thought to be important in determining of invasive ductal carcinoma cases with high grade and invasion ability. 

___

  • 1. Gewefel H, Salhia B. Breast cancer in adolescent and young adult women. Clin Breast Cancer. 2014; 14(6): 390-5.2. Rezaianzadeh A, Sepandi M, Akrami M, Tabatabaee H, Rajaeefard A, Tahmasebi S, et al. Pathological profile of patients with breast diseases in Shiraz. Asian Pac J Cancer Prev. 2014; 15(19): 8191-5.3. Tao Z, Shi A, Lu C, Song T, Zhang Z, Zhao J. Breast Cancer: Epidemiology and Etiology.Cell Biochem Biophys. 2015; 72(2): 333-8.4. Verma R, Bowen RL, Slater SE, Mihaimeed F, Jones JL. Pathological and epidemiological factors associated with advanced stage at diagnosis of breast cancer. Br Med Bull. 2012; 103(1): 129-45.5. Gasparini G, Barbarechi M, Doglioni C. Exp of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer. Clin Cancer Res. 1995; 1(2): 189-98.6. Nakopoulou L, Michalopoulou A, Giannopoulou I, Tzonou A, Keramopoulos A, Lazaris AC, et al. bcl-2 protein expression is associated with a prognostically favorable phenotype in breast cancer irrespective of p53 immunostaining. Histopathology 1999; 34(4): 310-19.7. Winstanley JH, Leinster SJ, Cooke TG, Westley BR, Platt-Higgins AM, Rudland PS. Prognostic significance of cathepsin D in patients with breast cancer. Br J Cancer 1993; 67(4): 767-72.8. Nadji M, Fresno M, Nassiri M, Conner G, Herrero A, Morales AR. Cathepsin D in host stromal cells, but not in tumor cells, is associated with aggressive behaviour in node-negative breast cancer. Hum. Pathol. 1996; 27(9); 890-95.9. Contesso G, Jotti GS. Bonadonna G.: Tumor grade as a prognostic factor in primary breast cancer. Eur J Clin Oncol. 1989; 25(3): 403-9.10. Pradhan SP, Dash A, Choudhury S, Mishra DP. Robinson's cytological grading on aspirates of breast carcinoma and correlation with Bloom-Richardson's histological grading. J Evid Based Med Healthcare.2017; 4(2): 86-91.11. De Potter CR, Schelfhout AM. The neu-protein and breast cancer. Wirchows Arch 1995; 426(2): 107-15.12. Razumovic JJ, Petrovecki M, Uzarevic B, Gamulin S. Mutual predictive value of c-erbB-2 overexpression and various prognostic factors in ductal invasive breast carcinoma. Tumori 2000; 86(1): 30-6.13. Howard EM, Lau SK, Lyles RH, Birdsong GG, Tadros TS, Umbreit JN, et al. Correlation and expression of p53, Her-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast cancer population. Int J Clin Oncol. 2004; 9(3): 154-60.14. Kariya S, Ogawa Y, Nishioka A, Moriki T, Ohnishi T, Ito S, et al. Relationship between hormonal receptors, HER-2, p53 protein, Bcl-2, and MIB-1 status and the antitumor effects of neoadjuvant anthracycline-based chemotherapy in invasive breast cancer patients. Radiat Med 2005; 23(3): 189-94.15. Chintamani, Singhal V, Singh JP, Lyall A, Saxena S, Bansal A. Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? –A prospective clinical study. BMC Cancer 2004; 4: 48-57.16. Zhang GJ, Kimijima I, Abe R, Kanno M, Katagata N, Hara K, et al. Correlation between the expression of apoptosis related bcl-2 and p53 oncoproteins and the carcinogenesis and progression of breast carcinomas. Clin Cancer Res 1997;3(12): 2329-35.17. Zhang GJ, Kimijima I, Tsuchiya A, Abe R. The role of bcl-2 expression in breast carcinomas. Oncol Rep. 1998; 5(5): 1211-16.18. Quinn CM, Ostrowski JL, Harkins L, Rice AJ, Loney DP. Loss of bcl-2 expression in ductal carcinoma in situ of the breast relates to poor histological differantiation and to expression of p53 and c-erbB-2 proteins. Histopathology 1998; 33(6): 531-6.19. Takei H, Oyama T, Iino Y, Horiguchi J, Hikino T, Maemura M, et al. Clinical significance of immunohistochemical bcl-2 expression in invasive breast carcinoma. Oncol Rep. 1999; 6(3): 575-81.20. Zhang GJ, Tsuda H, Adachi I, Fukutomi T, Yamamoto H, Hirohashi S, et al. Prognostic indicators for breast cancer patients with one to three regional lymph node metastasis with special reference to alterations in expression levels of bcl-2, p53 and c-erbB-2 protein. Jpn J Clin Oncol. 1997; 27(6): 371-7.21. Eissa S, Labib R, Khalifa A, Swelam N, Khalil F, El-Shenawy AM. Regulator of apoptosis in human breast cancer. Clin Biochem. 1999; 32(5): 321-6.22. Hellemans P, van Dam PA, Weyler J, van Oosterom AT, Buytaert P, Van Marck E. Prognostic value of bcl-2 expression in invasive breast carcinoma. Br J Cancer 1995; 72(2): 354-60.23. Texeira C, Reed JC, Pratt MAC. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995; 55(17): 3902-7.24. Lee WY, Jin YT, Tzeng CC. Reciprocal expression of bcl-2 and p53 in breast ductal carcinoma. Anticancer Res 1996; 16(5A): 3007-12.25. Krajewski S, Thor AD, Edgerton SM, Moore DH 2nd, Krajewska M, Reed JC. Analysis of bax and bcl-2 expression in p53 immunopositive breast cancers. Clin Cancer Res. 1997; 3(2): 199-208.26. Brouillet JP, Theillet C, Maudelonde T, Defrenne A, Simony-Lafontaine J, Sertour J, et al. Cathepsin D assay in primary breast cancer and lymph nodes: relationship with c-myc, c-erb-B-2 and int-2 oncogene amplification and node invasiveness. Eur J Cancer 1990; 26(4): 437-41.27. Maudelonde T, Khalaf S, Garcia M, Freiss G, Duporte J, Benatia M, et al. ,Immunoenzymatic assay of Mr 52.000 cathepsin D in 182 breast cancer cytosols: low correlation with other prognostic parameters. Cancer Res. 1988; 48(2): 462-6. 28. Thorpe SM, Rochefort H, Garcia M, Freiss G, Christensen IJ, Khalaf S, et al. Association between high concentrations of Mr 52.000 cathepsin D and poor prognosis İn primary human breast cancer. Cancer Res. 1989; 49(21): 6008-14.29. Henry JA, McCarthy AL, Angus B, Westley BR, May FE, Nicholson S, et al. Prognostic significance of the estrogen-regulated protein cathepsin D in breast cancer. An immunohistochemical study. Cancer 1990; 65(2): 265-71.30. Kandalaft PL, Chang KL, Ahn CW, Traweek ST, Mehta P, Battifora H. Prognostic significance of immunohistochemical analysis of cathepsin D in low stage breast cancer. Cancer 1993; 71(9): 2756-63. 31. Hurlimann J, Gebhard S, Gomez F. Oestrogen receptor, progestrone receptor, pS2, ERD5, HSP 27 and cathepsin-D in invasive ductal breast carcinomas. Histopathology 1993; 23(3): 239-48.32. Armas OA, Gerald WL, Lesser ML, Arroyo CD, Norton L, Rosen PP. Immunohistochemical detection of cathepsin D in T2N0 M0 breast carcinoma. Am J Surg Pathol. 1994; 18(2): 158-66.33. Okamura K, Kobayashi I, Matsuo K, Kiyoshima T, Yamamoto K, Miyoshi A, et al. Immunohistochemical localization of cathepsin D, proliferating cell nuclear antigen and epidermal growth factor receptor in human breast carcinoma analysed by computer image analyser:correlation with histological grade and metastatic behaviour. Histopathology 1997; 31(6): 540-8.34. Domagala W, Striker G, Szadowska A, Dukowicz A, Weber K, Osborn M. Cathepsin D in invasive ductal NOS breast carcinoma as defined by immunohistochemistry. No correlation with survival at 5 years. Am J Pathol. 1992; 141(5): 1003-12.