Correlation between ER, PR, HER-2, Bcl-2, p53, proliferative and apoptotic indexes with HER-2 gene amplification and TOP2A gene amplification and deletion in four molecular subtypes of breast cancer

Abstract

The aim of our study was to investigate HER-2 and TOP2A gene status and their correlation with Bcl-2, p53, Ki67, ssDNA, and clinicopathological parameters in four molecular subtypes of breast cancer. Seventy-four paraffin-embedded samples are immunohistochemically studied for the expression of estrogen receptor (ER), progesterone receptor (PR), HER-2, p53, Bcl-2, ssDNA, and Ki67, while HER-2 and TOP2A gene status by fluorescence in situ hybridization was investigated in 60 samples. Luminal A and B subtypes were characterized with small tumor size, intermediate histological grade, negative lymph node, and metastatic status, while triple negative and HER-2 positive subtypes were associated with larger tumor size, poorly differentiated tumors, and positive lymph node status. p53, Ki67, and ssDNA expression was higher in triple negative and HER-2 positive than in luminal subtypes, while ER, PR, and Bcl-2 dominated in luminal subtypes. HER-2 gene status was higher in luminal B and HER-2 positive than in luminal A and triple negative subtypes, while TOP2A gene status was similar. HER-2 gene status positively correlated with TOP2A gene status, HER-2 receptor, and histological grade, while negative correlation characterized relationship between HER-2 gene status and ER, PR, and Bcl-2. The shortened overall survival period characterized patients from triple negative breast cancer subtype (18.7 months). HER-2 and TOP2A gene amplification showed a tendency to be associated with larger tumor size, positive lymph node status, high level of apoptotic and proliferative indexes, and low level of p53 and Bcl-2 expression, which all together indicate group of patients with similar outcome during the progression of the disease.

BCL2 as a Subtype-Specific Prognostic Marker for Breast Cancer

“…To the best of our knowledge, although there is no significant difference, patients with luminal B (HER2-negative and HER2-positive) and HER2-overexpression breast cancer with BCL2 expression tend to have good prognosis. This observation is supported by the results of previous studies that showed that BCL2 is inversely correlated with proliferative markers, such as Ki-67, and HER2-overexpression, and hence plays an antiproliferative role despite its antiapoptotic effect [ 27 28 ]. In luminal B (HER2-negative) breast cancer, which expresses a high Ki-67 level (threshold ≥20%), BCL2 expression is high, but BCL2 plays an antiproliferative role, resulting in a more favorable outcome compared to that of breast cancer with BCL2-negative expression.…”

Comparisons of the Clinicopathological Characteristics and the Expression of Tumor Biomarkers among Luminal, HER2-Enriched and Triple Negative Breast Cancer

“…Thus, our study indicated that the biomarkers related to cell proliferation and transformation may be served as the potential therapeutic targets for HEBC and TNBC patients. In this study, as high as 71.7% LBC expressed Bcl-2, which was consistent with the finding from Olivera et al, whereas the expression of this biomarker was only 22% and 26% respectively in HEBC and TNBC [20]. The Bcl-2 overexpression was associated with a favorable outcome [21] and the reduction in expression of Bcl-2 protein was associated with progression and aggressive form of disease [22].…”

Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study

“…A previous study also identified higher Ki67 expression levels in triple-negative and HER2-positive subtypes compared with the luminal subtypes (27). However, whether the levels of Ki67 are highest in the triple-negative or the HER2-positive subtype required further investigation.…”