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Inhibition of 3β-Hydroxysteroid Dehydrogenase Type 1 Suppresses Interleukin-6 in Breast Cancer
Yuan-Ching Chang1, Chi-Hsin Lin2, Jiunn-Chang Lin1
1Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
Background:
Recently, we demonstrated that the expression of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) in breast cancer is associated with shorter recurrence-free survival, and genetic or pharmacologic inhibition of HSD3B1 reduced colony formation and xenograft growth. However, the mechanisms are unclear.
Methods:
Triple-negative MDA-MB-231 and BT-20 breast cancer cells underwent HSD3B1 silencing. Microarray and bioinformatic analysis were performed. The interleukin-6 (IL-6) expression and secretion were evaluated using real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Clonogenic ability and cell viability were determined in the absence or presence of recombinant IL-6.
Results:
Functional and pathway enrichment analyses showed that HSD3B1 silencing modulates the expression of several growth factors and cytokines. Cells transfected with HSD3B1-targeting small interfering RNA or treated with an HSD3B1 inhibitor (trilostane) had decreased IL-6 expression and secretion. HSD3B1 inhibition reduced colony formation, which was partially rescued by IL-6 supplementation. The HSD3B1 knockdown enhanced paclitaxel sensitivity, and IL-6 treatment partially reversed the augmented cytotoxicity.
Conclusions:
Our findings suggest that the therapeutic potential of targeting HSD3B1 is in part mediated by IL-6 suppression.
Insights
Targeting 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) in breast cancer may work by reducing interleukin-6 (IL-6). Inhibiting HSD3B1 suppressed tumor growth and enhanced chemotherapy effectiveness, partly through IL-6 suppression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer patients with high HSD3B1 expression show poorer survival.
- HSD3B1 inhibition reduces breast cancer cell growth and xenograft tumor development.
- The precise mechanisms underlying HSD3B1's role in breast cancer remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which HSD3B1 influences breast cancer progression.
- To explore the relationship between HSD3B1, interleukin-6 (IL-6), and breast cancer cell behavior.
- To assess the therapeutic potential of targeting HSD3B1 in breast cancer treatment.
Main Methods:
- HSD3B1 was silenced in triple-negative breast cancer cell lines (MDA-MB-231, BT-20).
- Microarray and bioinformatic analyses were employed to assess gene expression changes.
- Interleukin-6 (IL-6) levels were quantified using qPCR and ELISA.
- Clonogenic assays and cell viability assays were performed with and without IL-6 supplementation.
Main Results:
- HSD3B1 silencing altered the expression of growth factors and cytokines.
- Inhibition of HSD3B1 led to decreased IL-6 expression and secretion.
- Reduced colony formation due to HSD3B1 inhibition was partially restored by IL-6.
- HSD3B1 knockdown increased sensitivity to paclitaxel, an effect partially reversed by IL-6.
Conclusions:
- The therapeutic benefits of targeting HSD3B1 in breast cancer are, in part, mediated by the suppression of IL-6.
- IL-6 plays a significant role in mediating the effects of HSD3B1 on breast cancer cell growth and drug sensitivity.
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