Leptin influences estrogen metabolism and increases DNA adduct formation in breast cancer cells

Objective: The elevated incidence of obesity has been paralleled with higher risks of breast cancer. High adiposity increases leptin secretion from adipose tissue, which in turn increases cancer cell proliferation. The interplay between leptin and estrogen is one of the mechanisms through which leptin influences breast carcinogenesis. An unbalanced estrogen metabolism increases the formations of catechol estrogen quinones, DNA adducts, and cancer mutations. This study aims to investigate the effect of leptin on some estrogen metabolic enzymes and DNA adduction in breast cancer cells.Methods: High performance liquid chromatography(HPLC) was performed to analyze the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Reporter gene assay, real time reverse transcription polymerase chain reaction(real time RT-PCR), and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes: Cytochrome P-4501B1(CYP1B1), Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase1(NQO1), and Catechol-O-methyl transferase(COMT).Results: Leptin significantly increased the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine.Furthermore, leptin significantly upregulated CYP1B1 promoter activity and protein expression. The luciferase promoter activities of NQO1 and m RNA levels were significantly reduced. Moreover, leptin greatly reduced the reporter activities of the COMT-P1 and COMT-P2 promoters and diminished the protein expression of COMT.Conclusions: Leptin increases DNA adduct levels in breast cancer cells partly by affecting key genes and enzymes involved in estrogen metabolism. Thus, increased focus should be directed toward leptin and its effects on the estrogen metabolic pathway as an effective approach against breast cancer.

Advances in the Correlation between Intestinal Microbiota and Breast Cancer Development

The intestinal microbiota has a symbiotic relationship with humans. It participates in some important physiological activities in the human body and has an important impact on human health. It has become a hot topic of research by scientists in recent years. Among them, the research on the correlation between intestinal microbiota and cancer has increased rapidly. At present, the incidence rate of breast cancer is increasing, which seriously endangers the health of women. More and more studies have found that the occurrence of breast cancer is related to intestinal microbiota, and its possible mechanism includes intestinal microbiota dysbiosis, estrogen metabolism changes, immune regulation, and the participation of intestinal microbiota metabolites, etc. With the further development of high-throughput sequencing technology, the research on the correlation between intestinal microbiota and breast cancer has become more in-depth, from a structural level confined to microorganisms to a more comprehensive system structure and function level. These research results provide a new research direction for the treatment of breast cancer. In order to further study the interaction between intestinal microbes and breast cancer, this article will comprehensively describe the intestinal microbiota and breast cancer from four aspects: intestinal microbial dysbiosis, altered estrogen metabolism, immune regulation, and intestinal microbial metabolites. It also reviews the application research of intestinal microbiota in breast cancer treatment, including the influence of intestinal microbiota on the effects of breast cancer radiotherapy and chemotherapy, probiotic therapy, and dietotherapy.

Polymorphisms of estrogen-metabolizing genes and breast cancer risk: a multigenic study

Background Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute to this effect. To examine this hypothesis, we conducted a case-control study to investigate the relationship between polymorphisms of genes responsible for estrogen biosynthesis （CYP17, cytochrome P450c17a and CYP19, aromatase cytochrome P450） and estrogen sulfation of inactivation （ SULT1 A1, sulfotransferasel A1 ） and the risk of breast cancer in Chinese women. Methods This study involved 213 breast cancer patients and 430 matched controls. PCR-based restriction fragment length polymorphism （RFLP） and short tandem repeat polymorphism （STRP） assays were used to detect the mononucleotide transition of CYP17 and SULT1A1 and tandem repeat polymorphism of CYP19. Logistic regression analyses were used to determine OR and 95% CI of each and all three high-risk genotypes, of all three genotypes combined, and of estrogen exposure factbrs. The relationship between each high-risk genotype and clinicalpathological characteristics were also assessed. Results The frequency of A2 allele of CYP17 was 49.8% in cases and 49. 1% in controls （P =0. 82）. The frequency of His allele of SULT1A1 was significantly higher in cases （ 13.6% ） than in controls （9. 5% ） （P 〈 0. 05 ）. There was also significant difference of the （TTTA）10 allele of CYP19 which was 12. 4% in cases and 8.2% in controls （P 〈0. 05）. When the CYP17 A2 allele, CYP19 （TITA）1o and SULT1A1 His allele were considered as the “putative high-risk” genotype, there was an increased risk of breast cancer with the number of high-risk genotypes in a dose-response effect （trend, P = 0. 05 ）. In multivariate analysis, the SULT1A1 genotype remained the most significant determinant for breast cancer, with OR =2. 37 （95% CI 1.23 - 4. 74） , followed by CYP19, with OR = 1.75 （95% CI 1.27 - 3.56）. The （TTTA）10 allele of CYP19 was associated with tumor size, and the His allele of SULT1 A1 associated with status of lymph node metastasis. Conclusions This study supports the hypothesis that breast cancer can be initiated by estrogen exposure and that estrogen metabolizing genes are involved in this mechanism. This multigenic model is useful for identifying individuals who are at higher risks of breast cancer.

Is There A Relationship between Polycystic Ovary Syndrome and Endometriosis?

The endocrinologic and metabolic abnormalities of women with polycystic ovary syndrome （PCOS） can result in a series of endometrial diseases. Abnormalities of hyperandrogenism and hyperinsulinemia that may be found in PCOS can elevate the levels of E2 indirectly, reduce progesterone secretion and induce some growth factors such as vascular endothelial growth factor （VEGF） and insulin-like growth factors （IGFs） over expression, which may have a major impact on endometriosis occurrence and development. We suppose that there is a possible connection between PCOS and endometriosis.