Impact of obesity on breast cancer recurrence and minimal residual disease

Brett L. Ecker, Jun Y. Lee, Christopher J. Sterner, Aaron C. Solomon, Dhruv K. Pant, Fei Shen, Javier Peraza, Lauren Vaught, Samyukta Mahendra, George K. Belka, Tien Chi Pan, Kathryn H. Schmitz, Lewis A. Chodosh

Research output: Contribution to journalArticle

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Abstract

Background: Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods: Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results: HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion: These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.

Original languageEnglish (US)
Article number41
JournalBreast Cancer Research
Volume21
Issue number1
DOIs
StatePublished - Mar 13 2019

Fingerprint

Residual Neoplasm
Obese Mice
Obesity
Breast Neoplasms
Recurrence
Adipose Tissue
Neoplasms
Triacetoneamine-N-Oxyl
Fats
RNA Sequence Analysis
Resistin
Fat-Restricted Diet
Glucose Intolerance
Survival
Doxycycline
Adiponectin
Hyperinsulinism
High Fat Diet
Somatomedins
Glucose Tolerance Test

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ecker, B. L., Lee, J. Y., Sterner, C. J., Solomon, A. C., Pant, D. K., Shen, F., ... Chodosh, L. A. (2019). Impact of obesity on breast cancer recurrence and minimal residual disease. Breast Cancer Research, 21(1), [41]. https://doi.org/10.1186/s13058-018-1087-7
Ecker, Brett L. ; Lee, Jun Y. ; Sterner, Christopher J. ; Solomon, Aaron C. ; Pant, Dhruv K. ; Shen, Fei ; Peraza, Javier ; Vaught, Lauren ; Mahendra, Samyukta ; Belka, George K. ; Pan, Tien Chi ; Schmitz, Kathryn H. ; Chodosh, Lewis A. / Impact of obesity on breast cancer recurrence and minimal residual disease. In: Breast Cancer Research. 2019 ; Vol. 21, No. 1.
@article{20bea63406d74844801473bd0644d1dc,
title = "Impact of obesity on breast cancer recurrence and minimal residual disease",
abstract = "Background: Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods: Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60{\%} kcal from fat) or a control low-fat diet (LFD; 10{\%} kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results: HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95{\%} CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95{\%} CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion: These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.",
author = "Ecker, {Brett L.} and Lee, {Jun Y.} and Sterner, {Christopher J.} and Solomon, {Aaron C.} and Pant, {Dhruv K.} and Fei Shen and Javier Peraza and Lauren Vaught and Samyukta Mahendra and Belka, {George K.} and Pan, {Tien Chi} and Schmitz, {Kathryn H.} and Chodosh, {Lewis A.}",
year = "2019",
month = "3",
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doi = "10.1186/s13058-018-1087-7",
language = "English (US)",
volume = "21",
journal = "Breast Cancer Research",
issn = "1465-5411",
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number = "1",

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Ecker, BL, Lee, JY, Sterner, CJ, Solomon, AC, Pant, DK, Shen, F, Peraza, J, Vaught, L, Mahendra, S, Belka, GK, Pan, TC, Schmitz, KH & Chodosh, LA 2019, 'Impact of obesity on breast cancer recurrence and minimal residual disease', Breast Cancer Research, vol. 21, no. 1, 41. https://doi.org/10.1186/s13058-018-1087-7

Impact of obesity on breast cancer recurrence and minimal residual disease. / Ecker, Brett L.; Lee, Jun Y.; Sterner, Christopher J.; Solomon, Aaron C.; Pant, Dhruv K.; Shen, Fei; Peraza, Javier; Vaught, Lauren; Mahendra, Samyukta; Belka, George K.; Pan, Tien Chi; Schmitz, Kathryn H.; Chodosh, Lewis A.

In: Breast Cancer Research, Vol. 21, No. 1, 41, 13.03.2019.

Research output: Contribution to journalArticle

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T1 - Impact of obesity on breast cancer recurrence and minimal residual disease

AU - Ecker, Brett L.

AU - Lee, Jun Y.

AU - Sterner, Christopher J.

AU - Solomon, Aaron C.

AU - Pant, Dhruv K.

AU - Shen, Fei

AU - Peraza, Javier

AU - Vaught, Lauren

AU - Mahendra, Samyukta

AU - Belka, George K.

AU - Pan, Tien Chi

AU - Schmitz, Kathryn H.

AU - Chodosh, Lewis A.

PY - 2019/3/13

Y1 - 2019/3/13

N2 - Background: Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods: Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results: HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion: These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.

AB - Background: Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods: Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results: HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion: These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.

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Ecker BL, Lee JY, Sterner CJ, Solomon AC, Pant DK, Shen F et al. Impact of obesity on breast cancer recurrence and minimal residual disease. Breast Cancer Research. 2019 Mar 13;21(1). 41. https://doi.org/10.1186/s13058-018-1087-7