Estrogen receptor α regulates the expression of syndecan-1 in human breast carcinoma cells

Abstract

Breast cancer (BC) is the primary cause of cancer-related mortality among women. Patients who express the estrogen receptor (ER), which mediates the tumorigenic effects of estrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to E2 is associated with aggressive malignant phenotypes, which lead to relapse. These BC subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis as well as the proliferation and invasiveness of cancer cells. We showed here that the activation of ER-alpha (ERα) by estrogens induces downregulation of SDC1 expression in ER(+) MCF7 cells but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER downregulator, led to subsequent SDC1 overexpression. E2-dependent downregulation of SDC1 expression required de novo protein synthesis and was antagonized by treatment with BAY 11-7085, an irreversible inhibitor of IκBα phosphorylation, which inhibits the activation of NFκB. Downregulation of SDC1 expression required ERα and activation of IKK, but was independent to downstream transcriptional regulators of NFκB. BAY 11-7085 prevented E2-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilized E2-activated ERα, leading to subsequent downregulation of SDC1 expression. Our results showed that sustained ER signaling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER(+) BC as well as the overexpression of SDC1 in hormone receptor-negative BC subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for BC as well as for other endocrine-associated cancers.

Proteoglycans as Mediators of Cancer Tissue Mechanics

“…Sdc-1 is also more abundant in the ER-negative tumors, suggesting that its expression marks this more aggressive breast cancer phenotype (Barbareschi et al, 2003;Baba et al, 2006;Qiao et al, 2019). This has been corroborated by reports showing that Sdc-1 expression is directly repressed by ER (Fleurot et al, 2019). In agreement with this, recent work described Sdc-1 as an important marker of CSC phenotype in inflammatory breast cancer -a subtype with a notoriously poor prognosis (Ibrahim et al, 2017).…”

Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors

“…Another study indicates that syndecan-1 silencing results in attenuated BC cell metastasis to the brain as migration across the blood–brain barrier and adhesion to the perivascular regions of the brain are reduced, while its overexpression has the opposite effect [ 137 ]. Of note, an inverse correlation was determined between syndecan-1 and ER expression in ER (α+) BC, whereas overexpression of syndecan-1 was identified in aggressive ERα-negative BC subtypes [ 138 ]. However, the effects of syndecan-1 seem to be hormone-dependent.…”

“…Shedding of syndecan-1 due to enzymatic cleavage initiates a switch from a proliferative to an invasive phenotype in an MCF-7 BC cell model [ 141 ]. These results suggest that syndecan-1 could be a therapeutic target for BC [ 138 ] or utilized as a predictive marker of response to neoadjuvant chemotherapy [ 142 ].…”

“…On the other hand, hormones and growth factors regulate PG expression. Thus, estrogen regulates the expression of syndecan-1, which acts as an antagonist of the ER and is overexpressed in hormone receptor-negative BC subtypes [ 138 ]. Moreover, estrogen regulates the expression of heparanase in carotid walls, whose enzymatic action intrinsically modulates the activities of heparin-binding growth factors [ 164 ] and, by extension, angiogenesis [ 131 ].…”

Comprehensive Transcriptomic Analysis Reveals Dysregulated Competing Endogenous RNA Network in Endocrine Resistant Breast Cancer Cells

“…Heparan sulfate degradation was increased in the presence of overexpressed heparanase induced by tamoxifen treatment in ER positive breast cancer, which may be able to promote tumor invasion and therefore confer tamoxifen resistance (46). In addition, the expression of syndecan-1, which has heparan sulfate chains and is able to promote cancer invasiveness, could be induced by ER suppression using selective ER down-regulators in breast cancer cells (47). It is possible that syndcan-1, with its glycosaminoglycan chains, accounts for endocrine resistance in breast cancer.…”