Μελέτη νέων παραμέτρων ως προγνωστικών δεικτών στον καρκίνο του μαστού

Abstract

Introduction. Breast cancer the most frequent type of cancer among women, is characterised by biological and clinical heterogeneity. The need for accurate characterisation of the disease has promoted the search and application of a series of markers which describe the biology of the tumour, the stage of the disease and predict the Response to adjuvant therapy. Next to the established markers that are widely accepted there is a number of recently introduced markers that require further investigation. The main goal of this study is to investigate the prognostic potential of the enzyme poly(A) polymerase (PAP) and at the same time evaluate in parallel a few other markers to whom a varying degree of prognostic or predictive value has been attributed, such as c-erbB- 2, PCNA, P53, bcl-2 and telomerase. The enzyme poly(A)polymerase is one of the components participating in the formation of the poly (A) tail. This structure is found in the 3'end of the eukaryotic mRNA and it contributes to the transport from the nucleus to the cytoplasm, to the stability and the translatability of mRNAs. Thus, it participates in the control of gene expression. Previous studies have attributed prognostic value to PAP in certain types of leukaemia and in breast cancer as well. Increased PAP enzymatic activity in tumour cytosols from breast cancer patients was associated with decreased overall and disease free survival. The present study attempts to further investigate and delineate the prognostic potential of PAP through the examination of the relation of PAP to a number of clinical and biological parameters. Results. The study comprises of two sections. In the first section the relation of PAP activity to a number of parameters was investigated in 211 recently operated breast cancer tumour samples. The parameters studied were: age, tumour size, histology, lymph node involvement, steroid receptors, the expression of the proliferation marker PCNA, the expression mutant P53, and the activity of the enzyme telomerase. In the second section PAP and few additional parameters (c-erbB-2, bcl-2, ploidy) were studied in 78 frozen samples for which survival data were available for a time period of three years. The following statistically significant correlations were obtained: 1. PAP activity and expression have a positive correlation to PCNA. 2. The above correlation is stronger in tumours of node negative patients but is lost in those of node positive patients. 3. PAP activity and expression is higher in tumours of node positive patients. 4. PAP activity has a positive correlation to oestrogen and progesterone receptor expression. 5. PAP activity has a positive correlation to telomerase activity. 6. PAP expression has a positive correlation to c-erbB-2 and negative to bcl-2 expression No statistically significant correlation was observed between PAP activity or expression and age, tumour size, grade, histologic type, and P53. For the 68 patients for whom survival data were available no statistically significant correlation could be observed between PAP expression and overall or disease free survival. The following correlations were found statistically significant: 1. PCNA expression had a positive correlation with tumour ploidy, P53 expression and was increased in ductal carcinomas. 2. Telomerase activity has an inverse correlation to age. 3. C-erbB-2 expression correlate with tumor size. 4. P53 expression was inversely related to oestrogen receptor content and the probability of disease recurrence and disease grade. 5. Bcl-2 expression had an inverse correlation to patient age and the probability of death. The above results confirm previous reports. Furthermore there was an effort to investigate the underlying mechanism leading to the variation of PAP activity in breast cancer. The levels of enzyme activity in relation to the levels and the isoforms of PAP expression were monitored in breast tumours and in the breast cancer cell line MCF-7. The results indicate that the increased PAP activity in breast tumours reflects overexpression of the corresponding protein. Conclusions. The results indicate that PAP activity is closely related to parameters reflecting cell proliferation such as PCNA, telomerase and estrogen receptor content. Thus PAP activity is associated with the rate of cellular proliferation. This attribute of PAP is enhanced when only tumours from node negative patients are investigated and in this category PAP can be considered a very accurate marker of cellular proliferation in accordance to previous observations. On the contrary in node positive patients this attribute is lost since PAP is dissociated from other proliferation markers. Thus increased activity due to increased expression of PAP dissociated from the proliferation rate of tumour cells may be a characteristic of tumours with metastatic potential. Further studies of PAP with additional groups of patients, elucidation of the mechanisms leading to PAP overexpression in breast cancer and its relationship to processes leading to metastasis will contribute to the assessment of the prognostic character and value of PAP in breast cancer.

Στην παρούσα μελέτη έγινε προσπάθεια αποσαφήνισης του προγνωστικού ρόλου της πολύ(Α)πολυμεράσης στον καρκίνο του μαστού κυρίως μέσω της διερεύνησης της σχέσης της πολύ(Α)πολυμεράσης με μια σειρά κλινικοπαθολογικές και βιολογικές παραμέτρους. Μελετήθηκε η σχέση της PAP με μια σειρά παραμέτρους (ηλικία, μέγεθος όγκου, ιστολογικός τύπος, Grade, κατάσταση λεμφαδένων, υποδοχείς οιστρογόνων και προγεστερόνης, έκφραση του PCNA, mtP53, bcl-2, και τελομεράσης) σε δύο ομάδες δειγμάτων από όγκους μαστού. Από την ανάλυση των αποτελεσμάτων προέκυψαν τα παρακάτω συμπεράσματα. Η έκφραση της πολύ(Α)πολυμεράσης συνδέεται με τον ρυθμό πολλαπλασιασμού των καρκινικών κυττάρων. Η σχέση αυτή είναι πιο έντονη στους όγκους που είναι αρνητικοί για λεμφαδένες. Σε μια ομάδα όγκων όπου η πολύ(Α)πολυμεράση δεν σχετίζεται με τον κυτταρικό πολλαπλασιασμό είναι πιθανό τα επίπεδά της να σχετίζονται με την μεταστατική ικανότητα του όγκου.