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

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Breast cancer (BC) remains a leading cause of cancer mortality in women.
• Estrogen receptor (ER) expression is crucial for response to antihormonal therapy.
• Loss of ER expression or resistance to estrogen (E2) is linked to aggressive BC phenotypes and relapse.

Purpose of the Study:

• To investigate the relationship between estrogen receptor alpha (ERα) signaling and syndecan-1 (SDC1) expression in breast cancer.
• To elucidate the molecular mechanisms underlying SDC1 regulation by ERα.
• To identify SDC1 as a potential therapeutic target in ER-positive and hormone receptor-negative BC.

Main Methods:

• Utilized ER(+) MCF7 and T47D breast cancer cell lines.
• Employed RNA interference and selective ER downregulators to modulate ERα expression.
• Investigated the role of NFκB signaling pathway components, including IKK and IκBα phosphorylation, using inhibitors like BAY 11-7085.
• Assessed protein synthesis and ERα phosphorylation at Ser118.

Main Results:

• Estrogen (E2) activation of ERα downregulated SDC1 expression in MCF7 cells, but not T47D cells.
• Loss of ERα expression led to subsequent SDC1 overexpression.
• E2-dependent SDC1 downregulation required de novo protein synthesis and was antagonized by BAY 11-7085, an NFκB inhibitor.
• ERα and IKK activation were necessary for SDC1 downregulation, independent of downstream NFκB targets.
• BAY 11-7085 interfered with E2-mediated ERα phosphorylation, suggesting IKK stabilizes E2-activated ERα.

Conclusions:

• Sustained ER signaling effectively inhibits SDC1 expression.
• An inverse correlation exists between SDC1 and ER expression in ER(+) BC.
• SDC1 is overexpressed in aggressive, hormone receptor-negative BC subtypes.
• SDC1 represents a promising therapeutic target for breast cancer and other endocrine-associated malignancies.