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

Abstract

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.

The 100 top-cited articles in menopausal syndrome: a bibliometric analysis

“…cCNE2 may be a candidate gene for estrogen-progestininduced breast cancer. But strong evidence is still lacking to support for common genetic variants altering the effect of MHT on breast cancer risk in estrogen-progestin MHT combinations or in estrogen receptor (ER) positive cases [58,59]. The gut microbiota can influence breast carcinogenesis, but it remains to be investigated whether there are differences in the abundance, diversity, and composition of the gut microbiota between postmenopausal breast cancer patients and controls [60,61].Lack of physical activity, high postmenopausal body mass index, alcohol consumption, and use of menopausal hormone therapy are known risk factors for breast cancer [62][63][64].…”

GPD1 inhibits the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid metabolism signaling pathway

“…And the estrogen levels were strongly correlated with survival in breast cancer patients by the TCGA database ( Fig. 5 B) [ [29] , [30] , [31] ]. The survival probability of pre-menopause was higher than post-menopause in GPD1 low/medium expression levels not only, but also in GPD1 high expression levels.…”

Effects of mind-body exercise on perimenopausal and postmenopausal women: a systematic review and meta-analysis

“…A ccording to the World Health Organization, the global population of postmenopausal women is projected to reach 1.2 billion by 2030 and over 1.6 billion by 2050. 1,2 An increasing number of women are entering menopause. 3,4 Sleep disorders, anxiety, depression, osteoporosis, and other menopausal symptoms, affecting 75% to 85% of this demographic, significantly impact their quality of life.…”

“…According to the World Health Organization, the global population of postmenopausal women is projected to reach 1.2 billion by 2030 and over 1.6 billion by 2050 1,2 . An increasing number of women are entering menopause 3,4 .…”