The Effect of Menopausal Hormone Therapies on Breast Cancer

Flores, Valerie A.; Taylor, Hugh S.

doi:10.1016/j.ecl.2015.05.007

Cited by 8 publications

(9 citation statements)

References 91 publications

(132 reference statements)

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“…There is growing consensus that short term use of HT for peri-menopausal symptoms provides considerable benefit without undue cancer risk, whereas long term postmenopausal use has cancer risks that outweigh other benefits [5]. HT-use has a wide variety of biological effects within breast tissue that may affect breast cancer risk [7]. These include changes to transcriptional programs that may result in epigenetic changes that persist long after HT has been discontinued.…”

Section: Discussionmentioning

confidence: 99%

“…Concern about the safety of HT was raised after the Women's Health Initiative clinical trials in 2002 indicated that combined (estrogen plus progestin) HT use increased breast cancer risk [6]. Since then, epidemiological efforts have focused on timing and duration of exposure and elucidating the mechanisms underlying the risk [7,8]. The current consensus is that estrogen alone therapy or short-term combined HT use (initiated around the time of menopause) does not appear to increase breast cancer risk.…”

Section: Introductionmentioning

confidence: 99%

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Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10 −7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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“…Lasco A et al (42) reported that the serum TG levels of 20 postmenopausal women It is known to be a multi-directional "hormone buffer" and to supplement hormones in the body, which explains why it has been used to treat menopause-related diseases. At the same time, since only a small amount of DHEA is in free circulation and DHEA is only converted into estrogen in the peripheral tissues, systemic estrogen-like adverse effects, such as cholelithiasis (24) and venous thromboembolic and ischemic stroke events (25), can be avoided (26). In addition, when the level of DHEA in humans reaches 7 μg/L, the saturation of invertase occurs during the conversion of DHEA into active sex hormones, helping avoid a state of excess sex hormone levels in women.…”

Section: Dhea Alleviates Dyslipidemia In Postmenopausal Womenmentioning

confidence: 99%

Effect of dehydroepiandrosterone on atherosclerosis in postmenopausal women

Zhang

Zhou

et al. 2021

BST

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“…The commonly used MHT therapies were classified into estrogen treatment (ET) and estrogen plus progestogens treatment (EPT) [ 6 , 7 ]. The differences in breast cancer risk caused by estrogen combinations with different progestogens confused people using MHT [ 8 , 9 , 10 , 11 ], leading to a growing number of women avoiding MHT [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis

Deng

Huang

Shi

et al. 2022

IJMS

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Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle (CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3) were validated by RT-qPCR. Specifically, these seven DEGs were increased in EPT compared to ET (p < 0.05) and had higher expression levels in breast cancer than adjacent normal tissues (p < 0.05). Next, we found that estrogen receptor (ER)-positive breast cancer patients with a higher CNNE2 expression have a shorter overall survival time (p < 0.05), while this effect was not observed in the other six DEGs (p > 0.05). Interestingly, the molecular docking results showed that CCNE2 might bind to 17β-estradiol (−6.791 kcal/mol), progesterone (−6.847 kcal/mol), and medroxyprogesterone acetate (−6.314 kcal/mol) with a relatively strong binding affinity, respectively. Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT.

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The Effect of Menopausal Hormone Therapies on Breast Cancer

Cited by 8 publications

References 91 publications

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Effect of dehydroepiandrosterone on atherosclerosis in postmenopausal women

Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis

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