Abstract:Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ER)α-negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation
“…3 B). These results are in concordance with another study where higher levels of ERβ were found to be associated with favorable OS in inflammatory breast cancer patients 51 . Figure 3 ESR2 expression and association to overall survival (OS) and relapse-free interval (RFI) in the full SCAN-B cohort ( A , B ), the endocrine-treated sub-group ( C , D ) and the chemotherapy-treated subgroup ( E , F ).…”
Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = −0.18, p = 2.2e−16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
“…3 B). These results are in concordance with another study where higher levels of ERβ were found to be associated with favorable OS in inflammatory breast cancer patients 51 . Figure 3 ESR2 expression and association to overall survival (OS) and relapse-free interval (RFI) in the full SCAN-B cohort ( A , B ), the endocrine-treated sub-group ( C , D ) and the chemotherapy-treated subgroup ( E , F ).…”
Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = −0.18, p = 2.2e−16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
“…In a recent study, the anti-invasive effect of ERβ agonists was increased by GPER suppression ( Schmitz et al, 2022 ); however, ERβ1 did not directly regulate the expression of GPER mRNA. In ERa-negative inflammatory BC cells, ERβ1 suppresses cell migration via direct suppression of GPR141 expression (another GPCR) ( Thomas et al, 2021 ). Additionally, increased VEGF expression due to increased GPER expression promotes angiogenesis and cancer progression ( De Francesco et al, 2014 ).…”
Section: Mechanism Underlying the Roles Of Erβ Isoforms In Tnbc Progr...mentioning
Estrogen receptor β (ERβ) was discovered more than 20 years ago. However, the extent and role of ERβ expression in breast cancer remain controversial, especially in the context of triple-negative breast cancer (TNBC). ERβ exists as multiple isoforms, and a series of studies has revealed an inconsistent role of ERβ isoforms in TNBC. Our recent results demonstrated contrasting functions of ERβ1 and ERβ2/β5 in TNBC. Additional research should be conducted to explore the functions of individual ERβ isoforms and develop targeted drugs according to the relevant mechanisms. Consequently, a systematic review of ERβ isoforms is necessary. In this review, we overview the structure of ERβ isoforms and detail what is known about the function of ERβ isoforms in normal mammary tissue and breast cancer. Moreover, this review highlights the divergent features of ERβ isoforms in TNBC. This review also provides insights into the implications of targeting ERβ isoforms for clinical treatment. In conclusion, this review provides a framework delineating the roles and mechanisms of different ERβ isoforms in TNBC and sheds light on future directions for basic and clinical research.
“…ERβ is a ligand activated transcription factor that mediates effects of estrogen, along with ERα in different tissues during growth and development by regulating transcription of target genes. Tumor suppressive effects of ERβ have been documented in diverse cancer types such as thyroid, kidney, prostate, glioblastoma, ovarian and breast cancer [ 5 , 6 ]. A previous scientific report from our group was the first to look at ERβ levels in clinical specimens of IBC patients [ 6 ].…”
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confidence: 99%
“…Tumor suppressive effects of ERβ have been documented in diverse cancer types such as thyroid, kidney, prostate, glioblastoma, ovarian and breast cancer [ 5 , 6 ]. A previous scientific report from our group was the first to look at ERβ levels in clinical specimens of IBC patients [ 6 ]. Immunohistochemical analysis of IBC tumors revealed the association of higher expression of ERβ with significant improvement in metastasis free survival.…”
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confidence: 99%
“…The work from our group [ 6 ] establishes ERβ as a tumor suppressor in IBC by demonstrating its strong antimetastatic activity in preclinical models of the disease and delineating the mechanism of action. The findings of our study also shed new light onto the biology of IBC metastasis by discovering new roles for estrogen signaling in disease progression and identifying novel responsive genes that may function as drivers for aggressive phenotypes.…”
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