Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-06-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02262-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850137929534406656 |
|---|---|
| author | Amanda Caruso Felice Maria Accattatis Cinzia Giordano Luca Gelsomino Piercarlo Del Console Maria Francesca Fiorita Balazs Gyorffy Laura Bianchi Alfonso Carleo Rossana De Salvo Bruno M Simões Robert B Clarke Lorenzo Memeo Cristina Colarossi Eleonora Aiello Francesco Conforti Suzanne A W Fuqua Matilde Todaro Giorgio Stassi Catia Morelli Diego Sisci Daniela Bonofiglio Stefania Catalano Sebastiano Andò Ines Barone |
| author_facet | Amanda Caruso Felice Maria Accattatis Cinzia Giordano Luca Gelsomino Piercarlo Del Console Maria Francesca Fiorita Balazs Gyorffy Laura Bianchi Alfonso Carleo Rossana De Salvo Bruno M Simões Robert B Clarke Lorenzo Memeo Cristina Colarossi Eleonora Aiello Francesco Conforti Suzanne A W Fuqua Matilde Todaro Giorgio Stassi Catia Morelli Diego Sisci Daniela Bonofiglio Stefania Catalano Sebastiano Andò Ines Barone |
| author_sort | Amanda Caruso |
| collection | DOAJ |
| description | 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 (n = 375), and immunohistochemistry-based (n = 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-1high/TXNIPlow 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. |
| format | Article |
| id | doaj-art-b7e06099bd18460d97e3528566dd28dd |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-b7e06099bd18460d97e3528566dd28dd2025-08-20T02:30:42ZengBMCCell Communication and Signaling1478-811X2025-06-0123112010.1186/s12964-025-02262-4Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancerAmanda Caruso0Felice Maria Accattatis1Cinzia Giordano2Luca Gelsomino3Piercarlo Del Console4Maria Francesca Fiorita5Balazs Gyorffy6Laura Bianchi7Alfonso Carleo8Rossana De Salvo9Bruno M Simões10Robert B Clarke11Lorenzo Memeo12Cristina Colarossi13Eleonora Aiello14Francesco Conforti15Suzanne A W Fuqua16Matilde Todaro17Giorgio Stassi18Catia Morelli19Diego Sisci20Daniela Bonofiglio21Stefania Catalano22Sebastiano Andò23Ines Barone24Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Bioinformatics, Semmelweis UniversityLaboratory of Functional Proteomics, Department of Life Sciences, University of SienaLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of SalernoLaboratory of Functional Proteomics, Department of Life Sciences, University of SienaManchester Breast Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science CentreManchester Breast Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science CentrePathology Unit, Department of Experimental Oncology, Mediterranean Institute of OncologyPathology Unit, Department of Experimental Oncology, Mediterranean Institute of OncologyPathology Unit, Department of Experimental Oncology, Mediterranean Institute of OncologyDivision of Pathological Anatomy, Annunziata HospitalLester and Sue Smith Breast Center, Baylor College of MedicineDepartment of Health Promotion Sciences, Internal Medicine and Medical Specialties, University of PalermoDepartment of Precision Medicine in Medical, Surgical and Critical Care, University of PalermoDepartment of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)Department of Pharmacy, Health and Nutritional Sciences, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS)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 (n = 375), and immunohistochemistry-based (n = 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-1high/TXNIPlow 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.https://doi.org/10.1186/s12964-025-02262-4Breast CancerEndocrine resistanceAdipocytesTumor microenvironmentObesityIGF-1 |
| spellingShingle | Amanda Caruso Felice Maria Accattatis Cinzia Giordano Luca Gelsomino Piercarlo Del Console Maria Francesca Fiorita Balazs Gyorffy Laura Bianchi Alfonso Carleo Rossana De Salvo Bruno M Simões Robert B Clarke Lorenzo Memeo Cristina Colarossi Eleonora Aiello Francesco Conforti Suzanne A W Fuqua Matilde Todaro Giorgio Stassi Catia Morelli Diego Sisci Daniela Bonofiglio Stefania Catalano Sebastiano Andò Ines Barone Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer Cell Communication and Signaling Breast Cancer Endocrine resistance Adipocytes Tumor microenvironment Obesity IGF-1 |
| title | Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer |
| title_full | Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer |
| title_fullStr | Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer |
| title_full_unstemmed | Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer |
| title_short | Adipocyte/Tumor cell crosstalk via IGF-1/TXNIP axis promotes malignancy and endocrine resistance in breast cancer |
| title_sort | adipocyte tumor cell crosstalk via igf 1 txnip axis promotes malignancy and endocrine resistance in breast cancer |
| topic | Breast Cancer Endocrine resistance Adipocytes Tumor microenvironment Obesity IGF-1 |
| url | https://doi.org/10.1186/s12964-025-02262-4 |
| work_keys_str_mv | AT amandacaruso adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT felicemariaaccattatis adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT cinziagiordano adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT lucagelsomino adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT piercarlodelconsole adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT mariafrancescafiorita adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT balazsgyorffy adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT laurabianchi adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT alfonsocarleo adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT rossanadesalvo adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT brunomsimoes adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT robertbclarke adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT lorenzomemeo adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT cristinacolarossi adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT eleonoraaiello adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT francescoconforti adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT suzanneawfuqua adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT matildetodaro adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT giorgiostassi adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT catiamorelli adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT diegosisci adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT danielabonofiglio adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT stefaniacatalano adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT sebastianoando adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer AT inesbarone adipocytetumorcellcrosstalkviaigf1txnipaxispromotesmalignancyandendocrineresistanceinbreastcancer |