Normandie Univ, UNICAEN, OERECA, Caen, France.
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, Caen, France.
Endocr Relat Cancer. 2019 Jun;26(6):615-628. doi: 10.1530/ERC-18-0285.
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.
乳腺癌（BC）是女性癌症相关死亡的主要原因。表达雌激素受体（ER）的患者对抗激素治疗有反应，ER 介导雌激素的致癌作用。ER 表达丧失或对 E2 产生获得性耐药与侵袭性恶性表型相关，导致复发。这些 BC 亚型过度表达 syndecan-1（SDC1），一种跨膜硫酸乙酰肝素蛋白聚糖，介导血管生成以及癌细胞的增殖和侵袭。我们在这里表明，雌激素激活 ER-α（ERα）可诱导 ER（+）MCF7 细胞中 SDC1 表达下调，但在 T47D 细胞中则不诱导。RNA 干扰或选择性 ER 下调剂诱导的 ERα 表达丧失导致随后的 SDC1 过表达。E2 依赖性 SDC1 表达下调需要从头蛋白质合成，并被 BAY 11-7085 拮抗，BAY 11-7085 是 IκBα 磷酸化的不可逆抑制剂，可抑制 NFκB 的激活。SDC1 表达下调需要 ERα 和 IKK 的激活，但与 NFκB 的下游转录调节剂无关。BAY 11-7085 可阻止 E2 介导的 ERα 丝氨酸 118 磷酸化，增加其蛋白酶体降解，表明 IKK 稳定 E2 激活的 ERα，导致随后 SDC1 表达下调。我们的结果表明，持续的 ER 信号抑制 SDC1 的表达。这种拮抗作用阐明了 ER（+）BC 中 SDC1 与 ER 表达之间的负相关，以及激素受体阴性 BC 亚型中 SDC1 的过表达与最具侵袭性表型之间的负相关。这些结果表明 SDC1 是 BC 以及其他与内分泌相关的癌症的有吸引力的治疗靶点。
