Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance
Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanis...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/14/11441 |
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| author | Prathap Reddy Kallamadi Deepshika Esari Utkarsh Reddy Addi Rushendhiran Kesavan Uday Kumar Putcha Siddavaram Nagini Geereddy Bhanuprakash Reddy |
| author_facet | Prathap Reddy Kallamadi Deepshika Esari Utkarsh Reddy Addi Rushendhiran Kesavan Uday Kumar Putcha Siddavaram Nagini Geereddy Bhanuprakash Reddy |
| author_sort | Prathap Reddy Kallamadi |
| collection | DOAJ |
| description | Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts. |
| first_indexed | 2024-03-11T01:00:25Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:00:25Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2c929b85384c4c45893d96d5023f7b472023-11-18T19:39:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141144110.3390/ijms241411441Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose TolerancePrathap Reddy Kallamadi0Deepshika Esari1Utkarsh Reddy Addi2Rushendhiran Kesavan3Uday Kumar Putcha4Siddavaram Nagini5Geereddy Bhanuprakash Reddy6ICMR-National Institute of Nutrition, Hyderabad 500007, IndiaICMR-National Institute of Nutrition, Hyderabad 500007, IndiaICMR-National Institute of Nutrition, Hyderabad 500007, IndiaUT Southwestern Medical Center, Children Research Institute, Dallas, TX 75390, USAICMR-National Institute of Nutrition, Hyderabad 500007, IndiaDepartment of Biochemistry and Biotechnology, Annamalai University, Annamalinagar 608002, IndiaICMR-National Institute of Nutrition, Hyderabad 500007, IndiaPatients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.https://www.mdpi.com/1422-0067/24/14/11441breast cancerobesitymetabolic syndromeobese rat modelDMBAinsulin signaling |
| spellingShingle | Prathap Reddy Kallamadi Deepshika Esari Utkarsh Reddy Addi Rushendhiran Kesavan Uday Kumar Putcha Siddavaram Nagini Geereddy Bhanuprakash Reddy Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance International Journal of Molecular Sciences breast cancer obesity metabolic syndrome obese rat model DMBA insulin signaling |
| title | Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance |
| title_full | Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance |
| title_fullStr | Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance |
| title_full_unstemmed | Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance |
| title_short | Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance |
| title_sort | obesity associated with prediabetes increases the risk of breast cancer development and progression a study on an obese rat model with impaired glucose tolerance |
| topic | breast cancer obesity metabolic syndrome obese rat model DMBA insulin signaling |
| url | https://www.mdpi.com/1422-0067/24/14/11441 |
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