Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients

Abstract

Breast cancer is a heterogeneous disease displaying different histopathological characteristics, molecular profiling and clinical behavior. This study describes the expression patterns of senescence markers P53, DEC1 and DCR2 and assesses their significance on patient survival as a single or combined marker with P16 or P14 using breast cancer progression series. One thousand and eighty (1080) patients with primary invasive ductal carcinoma, no special type, were recruited through an 11-year retrospective study period. We constructed tissue microarrays of normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma from each patient and performed immunohistochemical staining to study the protein expression. Statistical analysis includes Pearson chi-square, Kaplan-Meier log ran test and Cox proportional hazard regression were undertaken to determine the associations and predict the survival outcomes. P53, DEC1 and DCR2 expression correlated significantly with normal, benign, premalignant and malignant tissues with (p<0.05). The expression profile of these genes increases from normal to benign to premalignant and plateaued from premalignant to malignant phenotype. There is a significant association between P53 protein expression and age, grade, staging, lymphovascular invasion, estrogen receptor, progesterone receptor and HER2 whereas DCR2 protein expression significantly correlated with tumour grade, hormone receptors status and HER2 (p<0.05 respectively). P53 overexpression correlated with increased risk of relapse (p = 0.002) specifically in patients who did not receive hormone therapy (p = 0.005) or chemotherapy (p<0.0001). The combination of P53+/P16+ is significantly correlated with poor overall and disease-free survival, whereas a combination of P53+/P14+ is associated with worse outcome in disease-free survival (p<0.05 respectively). P53 overexpression appears to be a univariate predictor of poor disease-free survival. The expression profiles of DEC1 and DCR2 do not appear to correlate with patient survival outcomes. The combination of P53 with P16, rather P53 expression alone, appears to provide more useful clinical information on patient survival outcomes in breast cancer.

Non-circadian aspects of BHLHE40 cellular function in cancer

“…As noted above, BHLHE40 can be expressed in both the nucleus and the cytoplasm, and its functional role in cancer may vary accordingly ( Figure 2B). BHLHE40 is upregulated in breast cancer compared to normal breast tissue [68][69][70][71][72] -and although the data presented do not refer to the localization of BHLHE40, accompanying immunohistochemical staining shows both nuclear as well as cytoplasmic staining in the tumor tissue [68,71,72]. The function of nuclear BHLHE40 was apparent from other studies, where nuclear BHLHE40 was up-regulated in MCF-7 estrogen receptor positive breast cancer cells www.Genes&Cancer.com upon paclitaxel treatment [103], suggesting that nuclear BHLHE40 prevent tumor progression.…”

“…In two studies of about 1200 breast cancer patients each, BHLHE40 was one of multiple markers predicting disease outcome and metastatic risk [69,70]. A fourth study of 1080 patients with primary invasive ductal carcinoma showed that BHLHE40 expression increased from normal to benign to premalignant and plateaued from premalignant to malignant phenotype [71]. Another study of 147 patients with invasive breast ductal carcinomas showed that BHLHE40 expression was elevated in invasive ductal carcinomas and positively correlated with tumor grade (P = 0.023) [72].…”

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

“…Senescent cells are more common in the normal tissues of aged individuals, especially in certain tissue types, such as skin and adipose tissue [ 38 , 39 , 40 ]. They are also present in cancer and in premalignant lesions and have been evaluated as prognostic markers [ 41 ]. The detection of senescence is complicated, as many of the molecules involved in senescence signalling are also oncogenes or tumour suppressors that may be up or down regulated as part of the carcinogenic process.…”

On the Origin of Carcinoma

“…The diagnosis of atypical hyperplasias increases the risk of being subsequently diagnosed with invasive cancer 40 . In hyperplasias, are common the detection of biomarkers of cellular senescence such as short telomeres, expression of the protein p16, and the infiltration of immune cells [41][42][43] . As it progresses to carcinoma, the recovery in the length of the telomeres, telomerase enzyme activity is observed while decreasing the presence of senescent cells 44,45 .…”