Mechanism of sestrin 3 inhibiting the proliferation of hormone receptor-positive breast cancer and enhancing the sensitivity to endocrine therapy via the mammalian target of rapamycin signaling axis

Tang Haozheng; Shu Dan; Liu Shengchun

doi:10.13406/j.cnki.cyxb.003935

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Mechanism of sestrin 3 inhibiting the proliferation of hormone receptor-positive breast cancer and enhancing the sensitivity to endocrine therapy via the mammalian target of rapamycin signaling axis

Clinical research | 更新时间：2025-11-20

- Mechanism of sestrin 3 inhibiting the proliferation of hormone receptor-positive breast cancer and enhancing the sensitivity to endocrine therapy via the mammalian target of rapamycin signaling axis
- Journal of Chongqing Medical University Vol. 50, Issue 11, Pages: 1558-1568(2025)
- 作者机构：
  
  重庆医科大学附属第一医院乳腺甲状腺外科，重庆　400016
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003935
  CLC： R737.9
- Received：07 April 2025，
  
  Revised：2025-06-17，
  
  Accepted：23 June 2025，
  
  Published：28 November 2025
- 稿件说明：
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汤昊铮,舒丹,刘胜春.SESN3通过mTOR信号轴抑制HR+乳腺癌增殖和促进内分泌治疗敏感性增加的机制研究[J].重庆医科大学学报,2025,50(11):1558-1568.

Tang Haozheng,Shu Dan,Liu Shengchun.Mechanism of sestrin 3 inhibiting the proliferation of hormone receptor-positive breast cancer and enhancing the sensitivity to endocrine therapy via the mammalian target of rapamycin signaling axis[J].Journal of Chongqing Medical University,2025,50(11):1558-1568.
汤昊铮,舒丹,刘胜春.SESN3通过mTOR信号轴抑制HR+乳腺癌增殖和促进内分泌治疗敏感性增加的机制研究[J].重庆医科大学学报,2025,50(11):1558-1568. DOI： 10.13406/j.cnki.cyxb.003935.

Tang Haozheng,Shu Dan,Liu Shengchun.Mechanism of sestrin 3 inhibiting the proliferation of hormone receptor-positive breast cancer and enhancing the sensitivity to endocrine therapy via the mammalian target of rapamycin signaling axis[J].Journal of Chongqing Medical University,2025,50(11):1558-1568. DOI： 10.13406/j.cnki.cyxb.003935.

摘要

目的

研究应激诱导蛋白Sestrin3（stress-induced protein sestrin3，SESN3）在激素受体阳性（hormone receptor+，HR+）乳腺癌（breast cancer，BC）中对于肿瘤的增殖能力以及内分泌治疗敏感性的影响及机制。

方法

通过癌症基因组图谱（the cancer genome Atlas，TCGA）数据库，分析BC组织和癌旁组织SESN3的表达情况；并收集BC组织和癌旁组织临床样本通过免疫组化（immunohistochemistry，IHC）芯片，验证SESN3的表达情况；同时蛋白质印迹法（Western blot）检测SESN3在不同病理亚型的BC细胞株中的蛋白表达情况。利用HR+BC细胞系构建过表达SESN3和敲减SESN3的模型，利用细胞计数试剂盒（cell counting kit-8，CCK-8）和集落形成实验检测细胞增殖能力，利用Western blot检测细胞周期变化，利用皮下荷瘤小鼠模型验证SESN3对体内增殖的影响。通过生物信息学分析和Western blot验证SESN3调控增殖的下游机制。

结果

TCGA数据库分析和临床样本均显示，SESN3基因在BC组织表达较癌旁组织更低，且SESN3高表达的患者无进展生存期更长，与其他亚型BC细胞系相比，HR+BC细胞系MCF-7和T-47D中SESN3表达较高。利用MCF-7和T-47D构建敲减（MCF-7

和T-47D

）和过表达（MCF-7

和T-47D

）的细胞模型，相较于对照组，MCF-7

和T-47D

细胞的增殖能力增加，在G2和M期的细胞分布更多。在体内成瘤实验中，MCF-7

组小鼠肿瘤生长明显增加。通过生信分析挖掘到哺乳动物雷帕霉素靶蛋白（mammalian Target of Rapamycin，mTOR）信号通路与SESN3呈负相关，经Western blot验证，MCF-7

和T-47D

的mTOR表达明显增加，且自噬相关基因的蛋白水平减少。接着，进一步验证了MCF-7

和T-47D

细胞对内分泌治疗敏感性降低。利用mTOR抑制剂依维莫司（everolimus，EVE）处理MCF-7、T-47D和MCF-7

、T-47D

，MCF-7

和T-47D

组增殖能力明显降低，由于mTOR通路调控细胞自噬减少导致内分泌治疗敏感性降低，在EVE处理之后MCF-7

、T-47D

细胞对内分泌治疗他莫昔芬（tamoxifen，TAM）的敏感性明显增加。

结论

通过整合数据库分析、临床样本验证及体内外模型实验验证，发现SESN3通过mTOR通路抑制HR+BC细胞的增殖，并增强内分泌治疗敏感性。

Abstract

Objective

To investigate the effect of the stress-induced protein sestrin 3（SESN3） on tumor proliferation and the sensitivity to endocrine therapy in hormone receptor-positive（HR+） breast cancer（BC） and its mechanism.

Methods

The cancer genome atlas（TCGA） database was used to analyze the expression level of SESN3 in breast cancer tissue and paracancerous tissue. The clinical samples of breast cancer tissue and paracancerous tissue were collected，and immunohistochemistry（IHC） microarray was used to validate the expression of SESN3. Western blot was used to measure the protein expression level of SESN3 in BC cell lines with different pathological subtypes. HR+BC cell lines were used to establish the models of SESN3 overexpression and knockdown，and cell counting kit-8（CCK-8） assay and colony formation assay were used to assess the proliferative capacity of cells； Western blot was used to analyze cell cycle alterations； a subcutaneous xenograft mouse model was used to validate the effect of SESN3 on proliferation

in vivo

. The bioinformatics analysis and Western blot were used to investigate the downstream mechanisms of SESN3 in regulating proliferation.

Results

The analysis of TCGA database and clinical samples showed that the expression of the SESN3 gene in BC tissue was significantly lower than that in paracancerous tissue，and the patients with high SESN3 expression had a longer progression-free survival time. Compared with the other subtypes of BC cell lines，the HR+ BC cells lines MCF-7 and T-47D had a relatively high expression level of SESN3. MCF-7 and T-47D cell lines were used to establish the cell models of knockdown（MCF-7

and T-47D

） and overexpression（MCF-7

nd T-47D

），and compared with the control group，MCF-7

and T-47D

cells showed increases in proliferative capacity and the proportion of cells arrested in the G2 and M phases.

In vivo

tumorigenesis experiments showed a significant increase in tumor growth in mice in the MCF-7

group. The bioinformatics analyses showed a significant negative correlation between the mammalian Target of Rapamycin（mTOR） signaling pathway and SESN3 expression，and Western blot validation showed a significant increase in the expression of mTOR in MCF-7

and T-47D

cells，as well as reductions in the protein expression levels of autophagy-related genes. Subsequently，we further confirmed that the knockdown of MCF-7 and T-47D cells led to a decreased sensitivity to endocrine therapy. In addition，MCF-7、T-47D、MCF-7

、and T-47D

cell lines were treated with the mTOR inhibitor everolimus（EVE），and there was a significant reduction in proliferative capacity in the MCF-7

group and the T-47D

group；since the mTOR pathway reduced the sensitivity to endocrine therapy by reducing cell apopto⁃sis，there was a significant increase in the sensitivity to endocrine therapy with tamoxifen（TAM）.

Conclusion

The integrated database analysis，clinical sample validation，and

in vivo

in vitro

experimental models show that SESN3 inhibits the proliferation of HR+ BC cells via the mTOR pathway and enhances the sensitivity to endocrine therapy.

关键词

Keywords

references

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