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Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer
Minhua Wu1, Jinhua Ding1, Limu Wen1
1Li Huili Hospital, Ningbo Medical Center, Ningbo 315040, China.
Objective:
The molecular mechanism of secondary resistance in Luminal breast cancer was studied to provide new ideas for the treatment of breast cancer.
Methods:
The sensitivity of the downregulation of myeloid leukemia factor 1-interacting proteins (MLF1IP) to Tamoxifen (TAM) was tested by the Cell Counting Kit-8 (CCK-8). The apoptosis of MLF1IP-mediated resistance was analyzed by flow cytometry (FCM) with/without TAM. Western blot was used in detecting various kinds of apoptosis and the expression of the protein related to the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to study the molecular mechanism of secondary endocrine resistance in Luminal breast cancer.
Results:
The downregulation of MLF1IP could significantly increase the drug sensitivity of Michigan Cancer Foundation-7 (MCF-7) cells and also inhibit the proliferation of MCF-7 cells under the stimulation of drugs. Western blot results showed that the expression of Bcl-2-associated X (BAX), Caspase3, Caspase7, and Caspase9 proteins increased when MLF1IP was downregulated. The results of the PI3K/AKT signaling pathway revealed that the phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression of MCF7-shRNA was higher than that of MCF7-NC cells, while the expression of p-AKT was lower than that of MCF7-NC cells.
Conclusions:
(1) MLF1IP-related apoptosis resistance plays an essential role in MLF1IP-mediated secondary resistance of breast cancer cells. (2) MLF1IP promotes AKT phosphorylation by inhibiting the PTEN expression, thus activating the PI3K/AKT signaling pathway and causing the secondary resistance of Luminal breast cancer. (3) MLF1IP can be used as a factor to predict the endocrine resistance of Luminal breast cancer.
Insights
Myeloid leukemia factor 1-interacting proteins (MLF1IP) downregulation enhances breast cancer cell sensitivity to Tamoxifen by promoting apoptosis. MLF1IP inhibition of PTEN activates AKT, driving secondary resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Secondary resistance to endocrine therapy is a major challenge in treating Luminal breast cancer.
- Understanding the molecular mechanisms underlying this resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the role of myeloid leukemia factor 1-interacting proteins (MLF1IP) in secondary endocrine resistance in Luminal breast cancer.
- To elucidate the molecular mechanism by which MLF1IP contributes to Tamoxifen resistance.
Main Methods:
- Cell Counting Kit-8 (CCK-8) assay to assess drug sensitivity.
- Flow cytometry (FCM) to analyze apoptosis.
- Western blot to detect apoptosis-related proteins and the PI3K/AKT signaling pathway.
Main Results:
- Downregulation of MLF1IP increased drug sensitivity and inhibited proliferation of MCF-7 cells.
- MLF1IP downregulation led to increased expression of BAX, Caspase3, Caspase7, and Caspase9.
- Inhibition of MLF1IP increased PTEN expression and decreased p-AKT, suggesting PI3K/AKT pathway modulation.
Conclusions:
- MLF1IP-mediated apoptosis resistance is key to secondary resistance in breast cancer.
- MLF1IP promotes AKT phosphorylation by inhibiting PTEN, activating the PI3K/AKT pathway and causing resistance.
- MLF1IP serves as a predictive factor for endocrine resistance in Luminal breast cancer.
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