Identification of the estrogen receptor beta as a possible new tamoxifen-sensitive target in diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients, ~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knock-out cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients.

An Integrated Study on the Differential Expression of the FOX Gene Family in Cancer and Their Response to Chemotherapy Drugs

“…Considering the importance of FOXO1 and specificity of FOXO4 in DLBC, we hypothesized that the combination of high expression of FOXO1 with low expression of FOXO4 could be diagnostic indicators for DLBC. Tamoxifen, an antiestrogen widely used in advanced ovarian and breast cancer has a therapeutic effect in DLBC by targeting estrogen receptor β [ 49 ]. In particular, we found the stimulation of Tamoxifen can reduce the expression of FOXO1 and increase the expression of FOXO4 .…”

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

“…According to the American Cancer Society Cancer Prevention Study-II Nutrition Cohort, a positive association between current postmenopausal combined use of estrogen and progestin and DLBCL has been observed [ 156 ]. Remarkably, increased expression of estrogen receptor-β (ERβ) has been detected in DLBCL cells [ 157 , 158 , 159 ]. Nuclear ERβ1 expression analysis in primary DLBCLs by immunohistochemistry revealed ERβ1 expression in 89% of the cases and was an independent prognostic factor for adverse progression-free survival in rituximab-chemotherapy treated DLBCL [ 157 ].…”

“…For nodal lymphoma, high ERβ expression (≥25%) was associated with poorer event-free survival independent of the international prognostic index with the adjusted hazard ratio (HR) of 2.49 (95% CI: 1.03–6.00, p = 0.042 [ 158 ]. ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL [ 159 ]. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduced cell viability in all tested DLBCL cell lines [ 159 ].…”

“…ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL [ 159 ]. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduced cell viability in all tested DLBCL cell lines [ 159 ]. In addition, tamoxifen-treated breast cancer patients showed a 38% reduced risk for DLBCL compared to breast cancer patients who did not receive tamoxifen [ 159 ].…”

“…Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduced cell viability in all tested DLBCL cell lines [ 159 ]. In addition, tamoxifen-treated breast cancer patients showed a 38% reduced risk for DLBCL compared to breast cancer patients who did not receive tamoxifen [ 159 ].…”