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管腔型乳腺癌继发性内分泌耐药的分子机制

Molecular Mechanism of Secondary Endocrine Resistance in Luminal Breast Cancer.

作者信息

Wu Minhua, Ding Jinhua, Wen Limu, Zhou Yuxin, Wu Weizhu

机构信息

Li Huili Hospital, Ningbo Medical Center, Ningbo 315040, China.

Medical School of Ningbo University, Ningbo 315040, China.

出版信息

Biomed Res Int. 2021 Mar 16;2021:6618519. doi: 10.1155/2021/6618519. eCollection 2021.

DOI:10.1155/2021/6618519
PMID:33816619
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7990544/
Abstract

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.

摘要

目的

研究腔面型乳腺癌继发性耐药的分子机制，为乳腺癌治疗提供新思路。

方法

采用细胞计数试剂盒-8（CCK-8）检测髓系白血病因子1相互作用蛋白（MLF1IP）下调对他莫昔芬（TAM）的敏感性。运用流式细胞术（FCM）分析有/无TAM情况下MLF1IP介导的耐药细胞凋亡情况。采用蛋白质免疫印迹法检测各种凋亡情况以及与磷脂酰肌醇3激酶（PI3K）/AKT信号通路相关蛋白的表达，以研究腔面型乳腺癌继发性内分泌耐药的分子机制。

结果

MLF1IP下调可显著提高密歇根癌症基金会-7（MCF-7）细胞的药物敏感性，并在药物刺激下抑制MCF-7细胞增殖。蛋白质免疫印迹结果显示，MLF1IP下调时，Bcl-2相关X蛋白（BAX）、半胱天冬酶3（Caspase3）、半胱天冬酶7（Caspase7）和半胱天冬酶9（Caspase9）的表达增加。PI3K/AKT信号通路结果显示，MCF7-shRNA细胞中第10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）蛋白表达高于MCF7-NC细胞，而p-AKT表达低于MCF7-NC细胞。

结论

（1）MLF1IP相关的凋亡抗性在MLF1IP介导的乳腺癌细胞继发性耐药中起重要作用。（2）MLF1IP通过抑制PTEN表达促进AKT磷酸化，从而激活PI3K/AKT信号通路并导致腔面型乳腺癌的继发性耐药。（3）MLF1IP可作为预测腔面型乳腺癌内分泌耐药的一个因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/e3c168124ba4/BMRI2021-6618519.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/0bccc794680d/BMRI2021-6618519.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/07e9a7e6c425/BMRI2021-6618519.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/6ff9d923b6c8/BMRI2021-6618519.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/82f85e612b64/BMRI2021-6618519.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/8ebbb58a8466/BMRI2021-6618519.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/e3c168124ba4/BMRI2021-6618519.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/0bccc794680d/BMRI2021-6618519.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/07e9a7e6c425/BMRI2021-6618519.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/6ff9d923b6c8/BMRI2021-6618519.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/82f85e612b64/BMRI2021-6618519.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/8ebbb58a8466/BMRI2021-6618519.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d25a/7990544/e3c168124ba4/BMRI2021-6618519.006.jpg

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