Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

Author:

Strømland Pouda Panahandeh1,Bertelsen Bjørn-Erik1,Viste Kristin1,Chatziioannou Anastasia Chrysovalantou2,Bellerba Federica3,Robinot Nivonirina2,Trolat Amarine2,Flågeng Marianne Hauglid1,Scalbert Augustin2,Keski-Rahkonen Pekka2,Sears Dorothy D.4,Bonanni Bernardo3,Gandini Sara3,Johansson Harriet3,Mellgren Gunnar1

Affiliation:

1. Haukeland University Hospital

2. International Agency for Research on Cancer, Nutrition and Metabolism Branch, Lyon, France

3. IEO, European Institute of Oncology IRCCS

4. Arizona State University

Abstract

Abstract Background Metformin reduces the incidence of breast cancer in patients with type 2 diabetes and obesity. However, our knowledge about the effects of metformin on cancer recurrence in breast tissue is limited. Therefore, in this study, we examined the breast tissue gene expression changes by metformin in breast cancer survivors. Methods Within the randomized placebo-controlled MetBreCS trial, baseline and one-year post-treatment fasting plasma and serum as well as breast tissue biopsies were collected. Breast cancer survivors with BMI >25 kg/m2 were randomly assigned to metformin (n=27), or placebo (n=13). We analyzed the transcriptomic profiles of the tissue biopsies by RNA sequencing. We also performed high-throughput metabolomics and sex steroid hormone analyses on the plasma and serum samples, respectively. To identify the metformin-associated signaling pathways in breast tissues, we integrated the gene expression and metabolomics and steroid hormone profiles using bivariate and functional analysis. Results Comparing breast tissue transcriptomic data, we identified MS4A1, HBA2, MT-RNR1 and MT-RNR2 expression to be differentially expressed in breast tissues from pre- and postmenopausal women. We also found significant metformin-associated down-regulation of EGFL6 and FDCSP in postmenopausal women. Long-term metformin treatment was significantly associated with decreased plasma levels of citrulline, arginine, PC ae C36:5, PC ae C38:6, caffeine, and 4-methyl-2-oxovalerate. The integration of transcriptomic and metabolomic profiles using bivariate correlation analysis followed by functional analysis revealed a down-regulation of immune response associated with the reduced plasma levels of arginine and citrulline in the pre- and postmenopausal metformin-treated group. The correlation between two steroid hormones (17β-estradiol, estrone) and global gene expression also showed an enrichment of steroid hormone biosynthesis and metabolism pathway with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Conclusions Our results indicate that breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors. Reduced levels of circulating arginine, citrulline, and estrogens in metformin-treated breast cancer survivors may also contribute to reducing recurrence risk in obesity-associated breast cancer. Trial registration MetBreCs trial was started in 2015 and is registered at European Union Clinical Trials Register (EudraCT Protocol #: 2015-001001-14) on 7 October 2015.

Publisher

Research Square Platform LLC

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3