Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer

Erin D. Giles, Sonali Jindal, Elizabeth A. Wellberg, Troy Schedin, Steven M. Anderson, Ann D. Thor, Dean P. Edwards, Paul S. MacLean, Pepper Schedin

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases. Methods: Here, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study. Results: Metformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism. Conclusions: These findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.

Original languageEnglish (US)
Article number50
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jun 14 2018

Fingerprint

Aromatase
Metformin
Rodentia
Breast Neoplasms
Neoplasms
Menopause
Weight Gain
Obesity
Neoadjuvant Therapy
Tumor Microenvironment
Adiposity
Ovariectomy
Hypoglycemic Agents
Estrogen Receptors
Type 2 Diabetes Mellitus
Macrophages
Body Weight
Lipids
Glucose
Survival

Keywords

  • Adipose
  • Liver
  • Macrophage
  • Metabolism
  • Obesity
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer. / Giles, Erin D.; Jindal, Sonali; Wellberg, Elizabeth A.; Schedin, Troy; Anderson, Steven M.; Thor, Ann D.; Edwards, Dean P.; MacLean, Paul S.; Schedin, Pepper.

In: Breast Cancer Research, Vol. 20, No. 1, 50, 14.06.2018.

Research output: Contribution to journalArticle

Giles, Erin D. ; Jindal, Sonali ; Wellberg, Elizabeth A. ; Schedin, Troy ; Anderson, Steven M. ; Thor, Ann D. ; Edwards, Dean P. ; MacLean, Paul S. ; Schedin, Pepper. / Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1.
@article{18f71235785e440ea0031ec23298c41d,
title = "Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer",
abstract = "Background: Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases. Methods: Here, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study. Results: Metformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism. Conclusions: These findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.",
keywords = "Adipose, Liver, Macrophage, Metabolism, Obesity, Tumor microenvironment",
author = "Giles, {Erin D.} and Sonali Jindal and Wellberg, {Elizabeth A.} and Troy Schedin and Anderson, {Steven M.} and Thor, {Ann D.} and Edwards, {Dean P.} and MacLean, {Paul S.} and Pepper Schedin",
year = "2018",
month = "6",
day = "14",
doi = "10.1186/s13058-018-0974-2",
language = "English (US)",
volume = "20",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer

AU - Giles, Erin D.

AU - Jindal, Sonali

AU - Wellberg, Elizabeth A.

AU - Schedin, Troy

AU - Anderson, Steven M.

AU - Thor, Ann D.

AU - Edwards, Dean P.

AU - MacLean, Paul S.

AU - Schedin, Pepper

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Background: Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases. Methods: Here, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study. Results: Metformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism. Conclusions: These findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.

AB - Background: Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases. Methods: Here, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study. Results: Metformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism. Conclusions: These findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.

KW - Adipose

KW - Liver

KW - Macrophage

KW - Metabolism

KW - Obesity

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85048526112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048526112&partnerID=8YFLogxK

U2 - 10.1186/s13058-018-0974-2

DO - 10.1186/s13058-018-0974-2

M3 - Article

VL - 20

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 50

ER -