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Updated: Aug 2, 2025
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
The estrogen/miR-338-3p/ADAM17 axis enhances the viability of breast cancer cells via suppressing NK cell's function
Yijiu Shi1,2, Jianhui Pan3, Chen Hang2
1Department of general surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
Natural killer (NK) cells are the critical elements of the innate immune response and implicated in rapidly recognizing and eliminating cancer cells. However, the tumor-suppressive ability of NK cells is often impaired in several cancer types. The critical roles of microRNAs have been elucidated by increasing evidences, while the regulation of miR-338-3p in anti-tumor activation of NK cells and its relationship with estrogen in breast cancer (BC) are still confusing. Here, miR-338-3p level was found to be significantly downregulated in BC tissues and estrogen receptor positive (ER+ ) cells, this difference was more obvious in ER+ patients or BC patients at advanced stage (TNM III and IV). MiR-338-3p level was shown to be downregulated by 17β-estradiol in BC cells (MDA-MB-231 cells and MCF-7) in vitro. MiR-338-3p overexpression decreased disintegrin and metalloprotease-17 (ADAM17) secretion in MDA-MB-231 (ER- ) and MCF-7 (ER+ ) cells. In addition, miR-338-3p overexpression or treatment with anti-ADAM17 antibody could down-regulate granzyme B, CD16, and NKG2D in NK cells, which was reversed by human recombinant ADAM17. Furthermore, these educated NK cells could promote the viability of MDA-MB-231 or MCF-7 cells. Taken together, our results demonstrate that miR-338-3p was negatively regulated by estrogen in BC cells, impairing NK cell's activity by the up-regulation of ADAM17, and conversely promoted the viability of BC cells. Therefore, the estrogen/miR-338-3p/ADAM17 axis is critically implicated in BC pathogenesis and may provide potential targets for BC diagnosis and treatment.
Insights
Estrogen downregulates miR-338-3p in breast cancer cells, impairing natural killer (NK) cell anti-tumor activity via ADAM17 upregulation. This estrogen/miR-338-3p/ADAM17 pathway promotes breast cancer progression.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Natural killer (NK) cells are crucial for innate immunity and cancer cell elimination.
- NK cell function is often impaired in various cancer types, including breast cancer (BC).
- The role of microRNAs, specifically miR-338-3p, and estrogen in regulating NK cell activity in BC remains unclear.
Purpose of the Study:
- To investigate the regulation of miR-338-3p by estrogen in breast cancer cells.
- To elucidate the impact of the miR-338-3p/ADAM17 axis on NK cell anti-tumor functions.
- To explore the potential therapeutic implications of the estrogen/miR-338-3p/ADAM17 pathway in BC.
Main Methods:
- Quantification of miR-338-3p levels in BC tissues and cells.
- In vitro experiments assessing the effect of 17β-estradiol on miR-338-3p expression.
- Analysis of ADAM17 secretion and its impact on NK cell markers (granzyme B, CD16, NKG2D) following miR-338-3p modulation.
- Assessment of NK cell-mediated tumor cell viability.
Main Results:
- miR-338-3p was significantly downregulated in BC tissues and estrogen receptor-positive (ER+) cells, particularly in advanced stages.
- 17β-estradiol treatment reduced miR-338-3p levels in BC cells.
- miR-338-3p overexpression decreased ADAM17 secretion, which in turn downregulated NK cell activation markers.
- Impaired NK cell activity, mediated by the miR-338-3p/ADAM17 axis, promoted BC cell viability.
Conclusions:
- Estrogen negatively regulates miR-338-3p in breast cancer cells.
- The estrogen/miR-338-3p/ADAM17 pathway impairs NK cell anti-tumor immunity.
- This axis plays a critical role in BC pathogenesis and presents potential therapeutic targets.
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