ABSTRACT
Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention as a prognostic factor in breast cancer. We aimed to validate the influence of Ep-CAM RNA expression in untreated node-negative breast cancer. Ep-CAM RNA expression was evaluated utilizing microarray-based gene-expression profiling in 194 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting. The prognostic significance of Ep-CAM RNA expression for disease-free survival (DFS), metastasis-free survival (MFS), and breast cancer-specific overall survival (OS) was evaluated in univariate and multivariate analysis adjusted for age, grading, pTstage, ER as well as PR receptor and HER-2 status. Additionally, Ep-CAM RNA expression was compared with immunohistochemistry (IHC) for Ep-CAM in 194 patients. The prognostic impact of Ep-CAM gene expression was validated in further 588 node-negative breast cancer patients. Levels of Ep-CAM RNA expression showed a significant correlation with IHC (P = 0.001) and predicted in univariate analysis DFS (P = 0.001, HR = 2.4), MFS (P = 0.003, HR = 2.5), and OS (P = 0.002, HR = 3.1) accurately. The prognostic influence of Ep-CAM RNA was significant also in multivariate analysis for DFS (P = 0.017, HR = 2.0), MFS (P = 0.049, HR = 1.9), and OS (P = 0.042, HR = 2.3), respectively. The association with MFS was confirmed in an independent validation cohort in univariate (P = 0.006, HR = 1.9) and multivariate (P = 0.035, HR = 1.7) analysis. Ep-CAM RNA correlated with the proliferation metagene (P < 0.001, R=0.425) Nevertheless, in multivariate analysis, Ep-CAM was associated with MFS independent from the proliferation metagene (P = 0.030, HR = 1.8). In conclusion, Ep-CAM RNA expression is associated with poor MFS in three cohorts of untreated node-negative breast cancer.
Subject(s)
Antigens, Neoplasm/genetics , Breast Neoplasms/genetics , Cell Adhesion Molecules/genetics , Gene Expression Regulation, Neoplastic , Lymph Nodes/pathology , RNA/genetics , Aged , Cell Proliferation , Cohort Studies , Disease-Free Survival , Epithelial Cell Adhesion Molecule , Female , Humans , Immunohistochemistry/methods , Lymphatic Metastasis , Middle Aged , Multivariate Analysis , Neoplasm Metastasis , PrognosisABSTRACT
INTRODUCTION AND HYPOTHESIS: This study evaluates the expression of estrogen receptor (ER) isoforms alpha (α) and beta (ß) and progesterone receptor (PR) in vaginal and periurethral tissue in women with genital prolapse in relation to genital and lower urinary tract symptoms (LUTS). METHODS: Forty-seven postmenopausal women without systemic estrogen therapy underwent pelvic organ prolapse quantification and urodynamic assessment. LUTS were evaluated by CATI questionnaire. Biopsies from vaginal and periurethral tissue were obtained during prolapse surgery. The steroid receptor gene expression was measured by RT-PCR. RESULTS: The expression of PR in periurethral and ER ß in vaginal tissue varied with prolapse extent. Nulliparous women showed a significantly higher expression of PR in periurethral tissue. Women with a positive stress test and those with overactive bladder symptoms showed a significantly lower amount of PR in vaginal tissue. CONCLUSION: Changes in PR expression in vaginal or periurethral tissue might be a marker of structural and endocrine changes.
Subject(s)
Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Pelvic Organ Prolapse/metabolism , RNA, Messenger/metabolism , Receptors, Progesterone/metabolism , Urethra/metabolism , Vagina/metabolism , Aged , Aged, 80 and over , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Female , Gynecological Examination , Humans , Middle Aged , Nocturia/complications , Nocturia/metabolism , Parity , Pelvic Organ Prolapse/complications , Pelvic Organ Prolapse/pathology , Pressure , Receptors, Progesterone/genetics , Surveys and Questionnaires , Urethra/physiopathology , Urinary Bladder, Overactive/complications , Urinary Bladder, Overactive/metabolism , Urinary Incontinence, Stress/complications , Urinary Incontinence, Stress/metabolism , Urinary Incontinence, Urge/complications , Urinary Incontinence, Urge/metabolism , UrodynamicsABSTRACT
PURPOSE: Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members. EXPERIMENTAL DESIGN: ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression. RESULTS: ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-x(L) could partially substitute for ERBB2 to antagonize tumor remission. CONCLUSIONS: Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets.
