Breast cancer is the primary cause of cancer-related mortality among women. Patients who express the oestrogen receptor (ER), which mediates the tumorigenic effects of oestrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to oestradiol is associated with aggressive malignant phenotypes, which lead to relapse. These breast cancer subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis, as well as the proliferation and invasiveness of cancer cells.

Fleurot et al. have shown that activation of ERα by oestrogens induces downregulation of SDC1 expression in ER-positive MCF7 cells, but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER down-regulator, led to subsequent SDC1 overexpression. Oestradiol-dependent down-regulation 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. Down-regulation of SDC1 expression required ERα and activation of IKK, but was independent of downstream transcriptional regulators of NFκB. BAY 11-7085 prevented oestradiol-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilised oestradiol-activated ERα, leading to subsequent down-regulation of SDC1 expression.

Results showed that sustained ER signalling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER-positive breast cancer, as well as the overexpression of SDC1 in hormone receptor-negative breast cancer subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for breast cancer, as well as for other endocrine-associated cancers.

Read the full article in Endocrine-Related Cancer doi:10.1530/ERC-18-0285