Diabetes, Metformin, and Breast Cancer in Postmenopausal Women

Chlebowski, Rowan T.; McTiernan, Anne; Wactawski‐Wende, Jean; Manson, Jo Ann E.; Aragaki, Aaron K.; Rohan, Thomas E.; Ipp, Eli; Kaklamani, Virginia; Vitolins, Mara Z.; Wallace, Robert B.; Gunter, Marc J.; Phillips, Lawrence S.; Strickler, Howard D.; Margolis, Karen L.; Euhus, David M.

doi:10.1200/jco.2011.39.7505

Cited by 179 publications

(147 citation statements)

References 53 publications

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“…A smaller study of 90 women with diabetes and breast cancer reported an increased frequency of progesterone receptor-positive breast tumours among metformin users 16 . Finally, a study from the U.S. Women's Health Initiative found that metformin users were less likely to present with invasive breast cancer; however, the authors did not explore the relationship between metformin and breast cancer stage 15 .…”

Section: Discussionmentioning

confidence: 99%

“…Whether metformin affects molecular breast cancer subtype is controversial. One study reported a reduction in hormone-sensitive tumours with metformin exposure 15 ; others reported either an increase 16,17 or no difference in hormone-positive tumours 14 . Those prior studies have been limited by small sample sizes, incomplete drug data, and inconsistent comparator groups and statistical methods.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, a study from the U.S. Women's Health Initiative found a reduction in invasive breast cancer among metformin users 15 . Whether metformin affects molecular breast cancer subtype is controversial.…”

Section: Introductionmentioning

confidence: 99%

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Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

et al. 2017

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PurposeThe objective of the present study was to use a large, population-based cohort to examine the association between metformin and breast cancer stage at diagnosis while accounting for mammography differences. MethodsWe used data from Ontario administrative health databases to identify women 68 years of age or older with diabetes and invasive breast cancer diagnosed from 1 January 2007 to 31 December 2012. Adjusted logistic regression models were used to compare breast cancer stage at diagnosis (stages i and ii vs. iii and iv) between the women exposed and not exposed to metformin. We also examined the association between metformin use and estrogen receptor status, tumour size, and lymph node status in the subset of women for whom those data were available. ResultsWe identified 3125 women with diabetes and breast cancer; 1519 (48.6%) had been exposed to metformin before their cancer diagnosis. Median age at breast cancer diagnosis was 76 years (interquartile range: 72-82 years), and mean duration of diabetes was 8.8 ± 5.9 years. In multivariable analyses, metformin exposure was not associated with an earlier stage of breast cancer (odds ratio: 0.98; 95% confidence interval: 0.81 to 1.19). In secondary analyses, metformin exposure was not associated with estrogen receptor-positive breast cancer, tumours larger than 2 cm, or positive lymph nodes. ConclusionsThis population-based study did not show an association between metformin use and breast cancer stage or tumour characteristics at diagnosis. Our study considered older women with long-standing diabetes, and therefore further studies in younger patients could be warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

et al. 2017

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“…Some pharmacoepidemiologic studies have suggested that metformin may have antineoplastic activity (21)(22)(23)(24)(25)(26)(27) but others have not supported this view (28)(29)(30)(31). Similarly, some (10) but not all (32) laboratory studies suggest that metformin has antineoplastic activity.…”

Section: Introductionmentioning

confidence: 99%

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

Javeshghani¹,

Zakikhani²,

Austin³

et al. 2012

Cancer Research

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Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. Cancer Res; 72(23); 6257-67. Ó2012 AACR.

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“…Emerging data suggest that metformin treatment is associated with reduced breast cancer incidence and mortality for individuals with type II diabetes [7,6,17]. For years, many studies have been done to investigate the possible direct and indirect effects of metformin on cancers of various origins.…”

Section: Diabetes Breast Cancer and Metforminmentioning

confidence: 99%

FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

Wellberg

Anderson

2014

HORM CANC

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Diabetes, Breast Cancer, and MetforminEmerging data suggest that metformin treatment is associated with reduced breast cancer incidence and mortality for individuals with type II diabetes [7,6,17]. For years, many studies have been done to investigate the possible direct and indirect effects of metformin on cancers of various origins. In diabetic patients, metformin improves metabolic function by promoting muscle glucose uptake and lowering hepatic gluconeogenesis [14,15,36]. In cultured cancer and normal cells, metformin has pleiotropic effects, including decreasing mitochondrial electron transport complex I activity, increasing the cellular AMP to ATP ratio, and activating the AMPK signaling pathway. The consequence of this is reduced protein translation, DNA synthesis, and cell proliferation. In isolated cancer stem-like cells (CSC), metformin's targets range from inflammation [13], to micro-RNAs [1], to the synthesis of nucleotide triphosphates [16]. The diversity of responses elicited by metformin from different tissues and from the specific cell types within those tissues suggests that metformin may be a valuable therapeutic for the treatment of a variety of cancers at many stages of tumor progression. Indeed, scores of clinical trials aiming to investigate the therapeutic effects of metformin for patients with cancer are either planned or ongoing. For breast cancer, large trials are open for patients with early-stage disease (NCT01101438) and metastatic disease (NCT01310231). The results of these trials are highly anticipated and will likely answer many lingering questions about the efficacy of metformin against cancer in nondiabetic patients. Short-term trials have also been conducted to evaluate the effects of metformin on breast tumor cell proliferation (NCT00897884) and tumor cell metabolism (NCT01266486).In this issue, Wahdan-Alaswad et al. demonstrate that in ER/PR/HER2-negative (triple negative (TN)) breast cancer cells metformin treatment targets fatty acid synthase (FASN) through a miR193b-dependent mechanism. Specifically, in TN breast cancer cells, metformin upregulated miR193b, which directly targeted the FASN mRNA resulting in decreased FASN protein levels. This was associated with reduced proliferation and increased apoptosis. Gene expression profiling also revealed changes in other metabolic enzymes, including members of the cholesterol biosynthesis pathway, suggesting that metformin may impact cancer cell lipid metabolism networks at multiple nodes. One limitation of this study is that the levels of cellular fatty acids were not quantified. Presumably, the amounts of de novo synthesized fatty acids correlate with the levels of FASN protein. In cancer cells, FASN expression is regulated by the HER2/Neu and PI3K signaling pathways, steroid hormones, and genomic amplification [20,34,37,42]; however, the spectrum of fatty acid products and the kinetics of the FASN reaction can be altered by effector proteins [21,32]. Interestingly, the effects of metformin on miR193b and FASN were only observe...

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Diabetes, Metformin, and Breast Cancer in Postmenopausal Women

Abstract: Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.

Cited by 179 publications

References 53 publications

Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

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