Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death

Abstract

Ki67 is a nuclear protein that is tightly linked to the cell cycle. It is a marker of cell proliferation and has been used to stratify good and poor prognostic categories in invasive breast cancer. Its correlation with gene expression patterns has not been fully elucidated. In this study, Ki67 immunohistochemistry using the MIB-1 antibody was performed on sections cut from 21 formalin-fixed, paraffin-embedded invasive breast cancers. Scoring was determined as nil (no immunostaining), low (10% or less immunopositivity) or high (410% immunoreactive cells) respectively. The relationship of Ki67 immunohistochemical detection with clinicopathologic parameters was evaluated. Using Affymetrix U133A GeneChips, expression profiles for these tumors were generated and correlated with Ki67 immunohistochemical findings. Analysis of variance was used to define genes that were differentially regulated between the groups. Real-time polymerase chain reaction (PCR) was used to confirm the presence of a downregulated gene. Our results showed high, low and nil Ki67 immunostaining in nine (43%), six (28.5%) and six (28.5%) invasive breast cancers respectively, with increased Ki67 protein expression correlating with high histologic grade (P ¼ 0.02), mitotic score (P ¼ 0.001) and estrogen receptor immunonegativity (P ¼ 0.002). Expression profiling trends of the Ki67 gene mirrored the observed proportions of immunostained cells when the Ki67 immunoscore was 410%. Genes related to apoptosis and cell death (bcl2, MAP2K4, TNF10) were noted to be downregulated in tumors that disclosed 440% Ki67 immunostaining (Po0.001). Downregulation of the bcl2 gene was confirmed at the RNA level by real-time RT-PCR. Differential regulation of these genes, especially bcl2, may contribute to the biological nature of clinically more aggressive and highly proliferative breast cancers.

Hyperthermia mediated by dextran-coated La0.7Sr0.3MnO3 nanoparticles: in vivo studies

“…Therefore, several researchers have correlated antitumor efficacy with reduction in Ki-67 expression. 28,29 The observed reduction of Ki-67 expression in our study also establishes antitumor efficacy of Dex-LSMO nanoparticles-mediated hyperthermia.…”

Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors

“…In cases where more than 10% of tumor cells are immunoreactive, immunostaining is regarded as positive 27,28 or high labeling index for Ki-67. 29 MUC1, MUC2, MUC5AC, and MUC6 protein expression status is positive when more than 20% of the tumor cells display immunoexpression in the cytoplasm. 27 The immunoexpression profiles of protein markers were evaluated in each case.…”

Stromal Signatures of Breast Carcinogenesis in Fibroadenoma—A Pilot Study

“…In breast cancer patients, Bcl-2 overexpression is associated with improved prognostic features including a low mitotic count, estrogen-receptor positivity, high histological grade of differentiation, a low cell proliferation rate, tumour necrosis, and DNA diploidy [15]. In this context, highly proliferative breast tumours associated with a poor prognosis often have Bcl-2 downregulation [16]. Lobular breast cancers express moderate to strong Bcl-2 positivity more often (80%) than ductal-type carcinomas (37%).…”