Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency
Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Zewdu Minas, Amy Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin W. Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs
Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Zewdu Minas, Amy Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin W. Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs
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Research Article Metabolism Oncology

Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency

Abstract

Diabetes 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.

Authors

Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Zewdu Minas, Amy Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin W. Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs

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Figure 5

Hyperglycemia induces breast cancer cell migration, invasion, and stemness.

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Hyperglycemia induces breast cancer cell migration, invasion, and stemne...
(A–C) Migration of breast cancer cells (MDA-MB-231, Hs578T, MDA-MB-468) under hyperglycemia. Shown are data for the 24-hour time point. Data represent mean ± SD of 4 replicates; Student’s t test was used. (D and E) Hs578T and MDA-MB-231 cells cultured under hyperglycemia develop an elongated morphology. Total original magnification, ×200. The scale bar is 100 µm. (F and G) Quantitative analysis of the elongated cell morphology in Hs578T and MDA-MB-231 cells cultured under hyperglycemia using the ImageJ software (NIH). Data represent average length of 100 cells from 5 different representative areas in each group; Wilcoxon’s test was used. (H) Matrigel invasion by Hs578T breast cancer cells under hyperglycemia. Shown are data for the 24-hour time point. Data represent mean ± SD of 5 replicates; Student’s t test was used. (I) Matrigel invasion by MDA-MB-231 breast cancer cells under hyperglycemia. Shown are data for the 24-hour time point. Data represent mean ± SD of 5 replicates; Student’s t test was used. (J) MDA-MB-231-LM2 cells harboring a stemness reporter were cultured with or without hyperglycemia. Number of SORE6+ cells among cultured MDA-MB-231-LM2-SORE6-mcherry breast cancer cells exposed to either 5 mM glucose (control) or hyperglycemia (25 mM glucose) for 48 hours. Hyperglycemia increases the number of SORE6+ cells, which is indicative of increased stemness. Addition of the positive control compound, TRULI, a Lats1/2 kinase inhibitor, increases the stemness signal. We did not observe SORE6+ cells among the control vector cells (MDA-MB-231-LM2-mCMV-mcherry) when cultured with or without 25 mM glucose. Data represent mean ± SD; Student’s t test was used for statistical analysis.