Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages
Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/4/543 |
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| author | Luca Gelsomino Cinzia Giordano Giusi La Camera Diego Sisci Stefania Marsico Antonella Campana Roberta Tarallo Antonio Rinaldi Suzanne Fuqua Antonella Leggio Fedora Grande Daniela Bonofiglio Sebastiano Andò Ines Barone Stefania Catalano |
| author_facet | Luca Gelsomino Cinzia Giordano Giusi La Camera Diego Sisci Stefania Marsico Antonella Campana Roberta Tarallo Antonio Rinaldi Suzanne Fuqua Antonella Leggio Fedora Grande Daniela Bonofiglio Sebastiano Andò Ines Barone Stefania Catalano |
| author_sort | Luca Gelsomino |
| collection | DOAJ |
| description | Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women. |
| first_indexed | 2024-03-10T20:42:29Z |
| format | Article |
| id | doaj.art-f431ce584830476ea122576bef8deafd |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T20:42:29Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-f431ce584830476ea122576bef8deafd2023-11-19T20:36:26ZengMDPI AGBiomolecules2218-273X2020-04-0110454310.3390/biom10040543Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of MacrophagesLuca Gelsomino0Cinzia Giordano1Giusi La Camera2Diego Sisci3Stefania Marsico4Antonella Campana5Roberta Tarallo6Antonio Rinaldi7Suzanne Fuqua8Antonella Leggio9Fedora Grande10Daniela Bonofiglio11Sebastiano Andò12Ines Barone13Stefania Catalano14Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi (SA), ItalyLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi (SA), ItalyLester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600 N1220.01 Alkek Building, Houston, TX 77030, USADepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyDepartment of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), ItalyObesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women.https://www.mdpi.com/2218-273X/10/4/543breast cancerendocrine resistanceleptinmacrophagesobesity |
| spellingShingle | Luca Gelsomino Cinzia Giordano Giusi La Camera Diego Sisci Stefania Marsico Antonella Campana Roberta Tarallo Antonio Rinaldi Suzanne Fuqua Antonella Leggio Fedora Grande Daniela Bonofiglio Sebastiano Andò Ines Barone Stefania Catalano Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages Biomolecules breast cancer endocrine resistance leptin macrophages obesity |
| title | Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages |
| title_full | Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages |
| title_fullStr | Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages |
| title_full_unstemmed | Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages |
| title_short | Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages |
| title_sort | leptin signaling contributes to aromatase inhibitor resistant breast cancer cell growth and activation of macrophages |
| topic | breast cancer endocrine resistance leptin macrophages obesity |
| url | https://www.mdpi.com/2218-273X/10/4/543 |
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