脂肪细胞/肿瘤细胞通过IGF-1/TXNIP轴的串扰促进乳腺癌的恶性肿瘤发生和内分泌抵抗。

Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer.

作者信息

Caruso Amanda, Accattatis Felice Maria, Giordano Cinzia, Gelsomino Luca, Del Console Piercarlo, Fiorita Maria Francesca, Gyorffy Balazs, Bianchi Laura, Carleo Alfonso, De Salvo Rossana, Simões Bruno M, Clarke Robert B, Memeo Lorenzo, Colarossi Cristina, Aiello Eleonora, Conforti Francesco, Fuqua Suzanne A W, Todaro Matilde, Stassi Giorgio, Morelli Catia, Sisci Diego, Bonofiglio Daniela, Catalano Stefania, Andò Sebastiano, Barone Ines

机构信息

Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), Cosenza, 87036, Italy.

Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), Cosenza, 87036, Italy.

出版信息

Cell Commun Signal. 2025 Jun 3;23(1):262. doi: 10.1186/s12964-025-02262-4.

DOI:10.1186/s12964-025-02262-4

PMID:40462107

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12135404/

Abstract

BACKGROUND

Despite significant improvements in the outcome of Estrogen Receptor (ER) α-positive breast cancer (BC) following the use of endocrine therapies, resistance remains a major challenge. Clinical studies proved that obesity, in addition to promote BC progression, is associated with a reduced efficacy to these treatments, but mechanisms remain unclear.

METHODS

We used co-culture systems followed by validation through an ‘ex vivo’ model of human mammary obese (Ob) adipocytes and obese endocrine-resistant metastatic Patient-Derived Organoids (PDOs). Transcriptomics with MixOmics-MINT and MetaCore Functional Tools along with lentiviral and pharmacological approaches provide insights into mechanisms. Clinical relevance was investigated using public datasets, transcriptome-based ( = 375), and immunohistochemistry-based ( = 65) evaluations.

RESULTS

In a model of co-culture, we demonstrated that conditioned media (CM) released by 3T3-L1A adipocytes reduced the sensitivity of parental MCF-7 BC cells to the inhibitory effects of Tamoxifen (Tam) on growth, motility and invasion and significantly increased the proliferative, motile and invasive phenotype of Tam-resistant (TR) BC cells. Transcriptomics identified TXNIP (Thioredoxin-interacting protein), a known tumor suppressor gene, as a network central hub, that was significantly down-regulated in CM-treated MCF-7 and TR cells. Accordingly, TXNIP expression was negatively correlated with Body Mass Index (BMI) in BC patients. Lentiviral TXNIP overexpression and pharmacological induction of TXNIP (i.e. SAHA) or the blockade of insulin-like growth factor-I (IGF-1) signaling, an obesity hallmark able to affect TXNIP expression, reversed CM-mediated effects. TXNIP down-regulation, proliferation and motility in TR cells were exacerbated by CM derived from Ob 3T3-L1A, and combination of an IGF-1 inhibitor and SAHA abrogated Ob-CM activities. Results were also validated in aromatase inhibitor-resistant BC cells. The effectiveness of IGF-1/TXNIP axis inhibition was confirmed using an ‘ex vivo’ model of human mammary obese adipocytes and PDO models. Finally, retrospective analyses demonstrated that an IGF-1/TXNIP signature was correlated with poorer survival in endocrine-treated BC patients.

CONCLUSIONS

In conclusion, our study sheds new light on adipocyte/BC cell crosstalk, underscoring the potential of targeting IGF-1/TXNIP axis to block this harmful connection, especially in the context of obesity.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s12964-025-02262-4.

摘要

背景

尽管使用内分泌疗法后雌激素受体（ER）α阳性乳腺癌（BC）的治疗效果有了显著改善，但耐药性仍然是一个主要挑战。临床研究证明，肥胖除了促进BC进展外，还与这些治疗的疗效降低有关，但其机制尚不清楚。

方法

我们使用共培养系统，随后通过人乳腺肥胖（Ob）脂肪细胞和肥胖内分泌耐药转移性患者来源类器官（PDO）的“体外”模型进行验证。使用MixOmics-MINT和MetaCore功能工具进行转录组学分析，以及慢病毒和药理学方法，以深入了解其机制。使用公共数据集、基于转录组（n = 375）和基于免疫组织化学（n = 65）的评估来研究临床相关性。

结果

在共培养模型中，我们证明3T3-L1A脂肪细胞释放的条件培养基（CM）降低了亲本MCF-7 BC细胞对他莫昔芬（Tam）对生长、运动和侵袭的抑制作用的敏感性，并显著增加了他莫昔芬耐药（TR）BC细胞的增殖、运动和侵袭表型。转录组学分析确定TXNIP（硫氧还蛋白相互作用蛋白），一个已知的肿瘤抑制基因，作为一个网络中心枢纽，在CM处理的MCF-7和TR细胞中显著下调。因此，TXNIP表达与BC患者的体重指数（BMI）呈负相关。慢病毒介导的TXNIP过表达以及TXNIP的药理学诱导（即SAHA）或胰岛素样生长因子-I（IGF-1）信号通路的阻断（一种能够影响TXNIP表达的肥胖特征），逆转了CM介导的作用。来自Ob 3T3-L1A的CM加剧了TR细胞中TXNIP的下调、增殖和运动，而IGF-1抑制剂和SAHA的联合使用消除了Ob-CM的活性。在芳香化酶抑制剂耐药的BC细胞中也验证了这些结果。使用人乳腺肥胖脂肪细胞的“体外”模型和PDO模型证实了IGF-1/TXNIP轴抑制的有效性。最后，回顾性分析表明，IGF-1/TXNIP特征与内分泌治疗的BC患者较差的生存率相关。