BCL3 expression is strongly associated with the occurrence of breast cancer relapse under tamoxifen treatment in a retrospective cohort study

Abstract

Patients with estrogen receptor positive breast cancer are usually receiving an anti-estrogen therapy by either aromatase inhibitors or selective estrogen receptor mediators such as tamoxifen. Nevertheless, acquired resistance to tamoxifen under treatment frequently hampers therapy. One proposed explanation for this phenomenon is the interaction of the tumor cells with cells of the tumor microenvironment via the Insulin-like growth factor RNA binding protein 5/B-cell lymphoma 3 (IGFBP5/BCL3) axis. Here we investigated whether a high expression of BCL3 either cytoplasmic or nuclear is associated with the occurrence of a relapse under anti-estrogen therapy in patients. Formaldehyde-fixed, paraffin-embedded samples of 180 breast cancer patients were analyzed for BCL3 expression by immunohistochemistry. An immunoreactive score (IRS) was calculated from staining intensity in cytoplasm and nucleus as well as the percentage of positive tumor cells. These scores were correlated with clinico-pathological parameters using cross-tabulation analysis and patients’ relapse free and overall survival by Kaplan–Meier analysis and Cox regression. A tamoxifen-adapted MCF-7 derived cell line was investigated for BCL3 localization by immunofluorescence. The cytosolic BCL3-IRS significantly correlated with the proliferation marker Ki-67, and with the occurrence of a relapse under tamoxifen treatment. Nuclear score correlated only with tamoxifen-relapse. In survival analysis, both scores were highly significant prognostic factors for relapse free, but not for overall survival. This was especially obvious for estrogen receptor positive and HER2/NEU negative cases as well as lobular breast cancer. Tamoxifen-treated, but not aromatase-treated patients had a poor survival when BCL3 scores were high. A tamoxifen adapted cell line exhibited a reduced expression and mainly nuclear localization of BCL3, compared to the parental estrogen receptor positive cell-line MCF-7. Altogether, these data strongly support a function of BCL3 in tamoxifen resistance and its potential use as a predictive biomarker for tamoxifen resistance.

Relationship of micro-RNA, mRNA and eIF Expression in Tamoxifen-Adapted MCF-7 Breast Cancer Cells: Impact of miR-1972 on Gene Expression, Proliferation and Migration

“…In these pathways, the NF-kB-inhibitor α (NFKBIA) represented one of the major hits. This is consistent with the data suggesting that NF-kB plays an important role in acquired tamoxifen resistance [ 52 , 53 , 54 , 55 , 56 ]. The result for the pathway leading to morphine addiction seems hard to explain; however, several effects of tamoxifen on morphine responses and vice versa have been published.…”

“…DOCK-AS2 was indeed moderately up-regulated in MCF-7 by 4OH tamoxifen (log 2 Fc = 0.5, p adj = 0.007); however, CTNNB1 was not. Interestingly, in thyroid cancer, this DOCK2-AS2 sponging was correlated with WNT-signalling, a pathway that is also supposed to be involved in tamoxifen resistance [ 56 , 74 , 75 ]. Nevertheless, possible sponging mechanisms on miR-1972 require further analysis.…”

ERβ1 Sensitizes and ERβ2 Desensitizes ERα-Positive Breast Cancer Cells to the Inhibitory Effects of Tamoxifen, Fulvestrant and Their Combination with All-Trans Retinoic Acid

“…By comparison, analysis of the role of the unique genes in MCF7-ERβ1 cells revealed that the regulation of all but one of the hub genes (PPARG, HIPK2, ZFP36L1, HMGB2 and ALDH1A3) and of 12 more unique genes (ASCL1, ID3, GPNMB, SGK3, BAG3, WDR73, ALKBH1, HIGD1A, FGD3, ACAA2, DOCK8 and AGR3) reportedly favors inhibition of breast cancer cell proliferation and tumorigenicity, induction of cell death and/or better clinical outcome [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. In contrast, in ERβ2-expressing cells, the regulation of the two unique hub genes (CXCL12 and SIX4) and of nine of the other unique genes (INHBE, GADD45B, RPS7, IFIT3, IGFBP3, JAG2, BCL3, GPR37L1 and KRT80) reportedly favors inhibition of cell death, resistance of BC to endocrine therapy and poor clinical prognosis [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. Indicative functions reported for all cell-death-related genes uniquely regulated in MCF7-WT, MCF7-ERβ1 and MCF7-ERβ2 cells are presented in Supplementary Tables S10–S12 .…”

A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

“…Clearly, the rise in CAIX expression in CAF-CM-treated cells is not linked to TIMP-1. We have previously shown by using MCF-7 cells that CAF-CM upregulates CAIX expression through a CAF-CM-induced increase in the expression of Bcl-3 [ 30 ], a IκB-like protein involved in anti-estrogen resistance [ 49 ]. CAIX has also been shown to play a role in drug resistance [ 47 ].…”