記住我
Research ArticleMetabolismOncology
Open Access | 
10.1172/jci.insight.170105
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Panigrahi, G. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by
Candia, J.
in:
JCI
|
PubMed
|
Google Scholar
|
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Dorsey, T. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by
Tang, W.
in:
JCI
|
PubMed
|
Google Scholar
|
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Ohara, Y. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Byun, J. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Minas, T. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Zhang, A. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Ajao, A. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Cellini, A. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Yfantis, H. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Flis, A. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Mann, D. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Ioffe, O. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Wang, X. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Liu, H. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Loffredo, C. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by Napoles, A. in: JCI | PubMed | Google Scholar
1Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
2Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
3Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, Maryland, USA.
4Division of Intramural Research, National Institute of Minority Health and Health Disparities, NIH, Bethesda, Maryland, USA.
5Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland, USA.
6Department of Pathology, University of Maryland Medical Center and Veterans Affairs Maryland Care System, Baltimore, Maryland, USA.
7Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
8Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Address correspondence to: Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Room 3050B, Bethesda, Maryland 20892-4258, USA. Phone: 240.760.6836; Email: ambss@mail.nih.gov.
Find articles by
Ambs, S.
in:
JCI
|
PubMed
|
Google Scholar
|
Published October 31, 2023 - More info
Published in Volume 8, Issue 23 on December 8, 2023
AbstractDiabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell–like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
Graphical Abstract
Introduction
Comorbidities like diabetes adversely affect patients with cancer with an increasing frequency (1, 2). They negatively and disproportionately affect underserved populations and may alter tumor biology and metastasis and the choice of treatment (3). Diabetes in patients with breast cancer is linked to an increased mortality (4, 5). In African American women, diabetes is associated with decreased breast cancer survival in patients independent of the tumor estrogen receptor (ER) status (6).
Diabetes is thought to promote cancer development and progression through hyperglycemia, altered insulin signaling, and excessive inflammation (7, 8). Metabolic health, rather than obesity, might be relevant for breast cancer risk stratification (9). Although studies that investigated the diabetes-induced tumor biology in patients with breast cancer remain sparse (10), multiple investigations have described the effect of hyperglycemia and diabetes in mouse models of breast cancer (10–14). In the 4T1 mouse model of breast cancer metastasis, hyperglycemia impaired tumor vascularization but enhanced metastatic seeding due to impaired secretion of granulocyte CSF and impaired neutrophil mobilization at the metastatic site (12). Other observations show that diabetes and hyperglycemia alter the human gut microbiome and induce intestinal barrier dysfunction and enhance the risk for infections (15). We previously reported that microbiome-derived metabolites can accumulate in breast tumors (16). Therefore, we hypothesized that diabetes may influence tumor biology in patients with breast cancer by mechanisms that may include the microbiome. Tumors in patients with diabetes may acquire distinct molecular signatures that alter disease aggressiveness and therapy response.
To examine how diabetes affects breast cancer biology, we used a discovery approach consisting of 3 human xenograft models for breast cancer that were orthotopically grown in diabetes-prone NRG-Akita mice. We investigated the tumor metabolome and transcriptome and then compared the contrasts between hyperglycemic and control mice with the contrasts in human breast tumors, comparing patients with diabetes and patients without diabetes. In addition, we cultured human breast cancer cell lines under hyperglycemia for further discovery and performed mechanistic studies to validate observations. Using this approach, we identified coherent biological differences related to hyperglycemia and diabetes in both ER– and ER+ breast cancer. Notably, our findings support the hypothesis that diabetes-associated breast tumors acquire a proinflammatory metabolome and a condition of DNA repair deficiency. Based on these observations, these tumors may show an increased response to DNA repair pathway inhibitors, which should be examined in clinical studies.
ResultsStudy design. The effects of diabetes and hyperglycemia on breast cancer biology have not been thoroughly investigated using clinical samples. Hyperglycemia is a hallmark of type 1 and type 2 diabetes, whereas insulin secretion is reduced or absent when diabetes is established (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.170105DS1) (17). We applied a 3-pronged approach to obtain a comprehensive assessment of diabetes-induced effects in xenograft breast tumors, patient tumors, and human breast cancer cell lines, as outlined in Supplemental Figure 1C. Our animal model for diabetes/hyperglycemia was NRG-Akita mouse based. We used female Akita mice that progressively develop hyperglycemia with an onset at 4 weeks of age as a model of genetically induced hyperglycemia with similarities to type 1 diabetes in disease origin but exhibiting some phenotypes of type 2 diabetes (18, 19). Fresh-frozen patient tumors were obtained from women with both type 1 diabetes (n = 6) and type 2 diabetes (n = 34). Most of these women were self-identified African Americans (n = 33), including all patients with type 1 diabetes. African American women are a high-risk group for aggressive forms of breast cancer and are generally more affected by diabetes than other women (6, 20).
Initially, we examined the hyperglycemia-induced biology of orthotopically grown tumors from 3 ER– human breast cancer cell lines, MDA-MB-231, MDA-MB-468, and Hs578T, injected into the abdominal mammary fat pad of either diabetes-prone Akita mice (NOD.Cg-Rag1tm1Mom Ins2Akita Il2rgtm1Wjl/SzJ) or its matched control (NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl/SzJ), all 8 weeks old. Tumor-bearing mice were sacrificed at 5 weeks for MDA-MB-231, 6 weeks for MDA-MB-468, or 8 weeks for Hs578T xenografts, as shown in Supplemental Figure 2A. At these time points, all Akita mice, but none of the controls, had developed hyperglycemia (n = 4–5 per group; Supplemental Figure 2B). Xenografts in hyperglycemic and control mice did not show significant differences in either tumor growth (Supplemental Figure 2C) or their proliferation score (Supplemental Figure 2D) across the 3 models. However, for the 1 cell line known to produce metastases from orthotopically grafted tumors, MDA-MB-231, we detected metastatic lesions in the spleen, kidney, and upper gastrointestinal tract in 2 of 4 tumor-bearing Akita mice (50%) but not in any of the 5 tumor-bearing control mice (Supplemental Figure 2E). Consistent with the xenograft growth data, hyperglycemia did not enhance proliferation in human breast cancer cells, irrespective of whether or not mannitol was added in the control experiments to adjust for osmolarity (Supplemental Figure 2F).
Hyperglycemia-induced metabolic alterations in breast tumor xenografts. Next, we investigated the metabolome profiles of the xenografts comparing tumors from hyperglycemic versus control mice (n = 4, each comparison group). Being able to detect up to 830 metabolites with the applied platform (Metabolon), we uncovered hyperglycemia-associated alterations in the tumor metabolome (Supplemental Table 1), as shown by the principal component analysis (PCA; including all metabolites) (Figure 1A) and a hierarchical cluster analysis that included all metabolites at a FDR < 0.3 (MDA-MB-231, n = 219; MDA-MB-468, n = 217; Hs578T, n = 443 metabolites; Figure 1B). These metabolic differences were also found in blood samples, with microbiome-derived 3-phenylpropionate and hippurate being the most upregulated serum metabolites in the presence of hyperglycemia, as shown for Akita mice bearing MDA-MB-468 xenografts (n = 4; Supplemental Table 1 and Supplemental Figure 3, A–D). Still, the hyperglycemia-associated metabolome contrasts for serum and tumor showed differences, with 341 metabolites being distinctively altered by hyperglycemia in serum and 91 metabolites in tumor xenografts, applying an FDR < 0.3 (Supplemental Figure 4). Across the 3 xenograft models, 71 tumor metabolites were commonly altered in the Akita mice (Figure 1C and Supplemental Table 2). Glucose was upregulated in all tumors of these mice, whereas intratumor 1,5-anhydroglucitol (1,5-AG), a known diabetes marker that is downregulated in the presence of hyperglycemia (21, 22), was greatly diminished (average 50-fold), consistent with diabetes/hyperglycemia-induced reprogramming of tumor metabolism (Figure 1D and Supplemental Figure 3, E and F). This observation was further confirmed with the concurrent accumulation of fructosyllysine (all xenografts) and N6-carboxylmethyllysine (CML) in MDA-MB-468 and Hs578T xenografts. Both metabolites belong to the family of food-derived, proinflammatory, and promutagenic advanced glycation end products that are commonly elevated in people with diabetes (23). Among the 71 tumor metabolites, 67 metabolites were either steadily increased (n = 53) or decreased (n = 14) in Akita mice (Figure 1C), with an FDR < 0.05 for each metabolite in the combined analysis across the 3 xenograft models (Supplemental Table 2). Notably, many of them represent food- or microbiome-derived metabolites that mostly accumulated in the tumors in presence of diabetes, whereas a small number of metabolites represent typical energy or tumor metabolism–related molecules (e.g., α-ketoglutarate, glucose). Food-derived metabolites include isoflavones like genistein and daidzein sulfate that may reduce the risk of breast cancer recurrence but may also interfere with the antitumor effects of breast cancer therapeutics (24, 25). At least 8 of the 71 diabetes/hyperglycemia-associated metabolites have previously been linked to the gut microbiome (26, 27) and included hippurate as the metabolite with the most significant accumulation, besides imidazole propionate, 3-phenylprorionate, or phenyl sulfate, among others (Supplemental Table 2). Hippurate, imidazole propionate, and phenyl sulfate have been reported to be increased in diabetes (26, 28, 29), consistent with our data. Last, we noticed that α-ketoglutarate, a key metabolite in the regulation and maintenance of the epigenome, was consistently downregulated in tumors of hyperglycemic mice. Interestingly, a loss of α-ketoglutarate–dependent lysine demethylase activity has recently been linked to a suppression of DNA repair by disrupting local chromatin signaling (30, 31).
Figure 1Hyperglycemia induces robust metabolite alterations in tumor xenografts. (A) Unsupervised PCA using the metabolite data obtained from xenografts grown in diabetic (_D) and nondiabetic mice (_ND). The plot shows data points for each of the MDA-MB-231, MDA-MB-468, and Hs578T xenografts and highlights the separation by diabetes status. (B) Heatmaps emphasizing the difference in intratumor metabolite abundance between diabetic and nondiabetic xenografts (FDR cutoff < 0.3 for inclusion of differential metabolites). The plots show the data from MDA-MB-231, MDA-MB-468, and Hs578T xenografts. (C) Venn diagram with 71 metabolites with levels altered by diabetes across MDA-MB-231, MDA-MB-468, and Hs578T xenografts (FDR < 0.05). Fifty-three of them were consistently upregulated, and 14 were downregulated in all xenografts of diabetic mice. (D) Intratumor levels of the diabetes markers, glucose, and 1,5 anhydroglucitol (1,5 AG), in MDA-MB-231, MDA-MB-468, and Hs578T xenografts by diabetes status. Data represent mean ± SD of log transformed relative abundance levels (n = 4 each group), with Student’s t test for significance testing.
The metabolome of diabetes-associated patient tumors. Having observed that diabetes-related hyperglycemia alters the metabolome of human breast tumor xenografts, we asked whether similar metabolic alterations can be detected in breast tumors from patients with diabetes. We analyzed the metabolome of tumors from 40 women with diabetes and 48 without diabetes and used the tumor ER status to match patients (Supplemental Table 3). Most of these patients were self-identified African American women. Patients with diabetes were older (65 versus 51.5 years of age) and tended to have a higher BMI (32.2 versus 29.2). Even so, independent of the diabetes status, most women in our patient cohort would best be categorized as overweight to obese, representing US trends for women in this age group. The metabolome contrast comparing patients with or without diabetes was consistent with the metabolome contrast in our experimental model of hyperglycemia — however less distinct — likely because patients were heterogenous with regard to their dietary intake and with regard to being treated with antidiabetic drugs. Nevertheless, when we choose an unadjusted P < 0.05 as the cutoff, a metabolome profile emerged that was consistent with findings in our xenograft-based discovery cohort (Supplemental Figure 3, G–I). Patients with diabetes presented with reduced intratumor 1,5-AG levels and an accumulation of microbiome-derived metabolites in their tumors, including trimethylamine N-oxide, imidazole propionate, cresol sulfate, and phenyl sulfate. Food-derived metabolites included the advanced glycation end product, CML. The intratumor accumulation of CML in patients with diabetes was robust and remained s
留言 (0)