Background: Genetic studies have found that a germlineBRCA1gene mutation is the origin of highly increased cancer risk. Clinical studies have suggested that increased cancer risk in type-2 diabetes may be attributed to unhealthy lifestyle factors and bad habits. Purpose: Patients with eitherBRCA1gene mutation or type-2 diabetes similarly exhibit increased cancer risk, insulin resistance, and fertility disorders. It was suggested that these three alterations derive from a common genomic failure, and its recognition may shed light on the unsolved secret of cancer. Results: (1) Germline mutations onESR1,BRCA1, andCYP19Agenes encoding estrogen receptor alpha (ERα), genome safeguarding BRCA1 protein, and CYP19 aromatase enzyme cause genomic instability.BRCA1andESR1gene mutations specifically cause breast cancer, while error in theCYP19Agene leads to cancers in the endometrium, ovaries, and thyroid. (2) ERα, BRCA1, and CYP19 aromatase proteins are transcription factors creating the crucial DNA stabilizer circuit driven by estrogen regulation. Liganded ERα drives a second regulatory circuit to also control cell proliferation, in partnership with various growth factors. In a third regulatory circuit, liganded ERα drives cellular glucose supply in close interplay with insulin, IGF-1, and glucose transporters. (3) Impaired expression or activation of each transcription factor of the triad leads to defective estrogen signaling and endangers regular cell proliferation, insulin sensitivity, and fertility. (4) Impaired estrogen signaling caused by either genetic or lifestyle factors alarms the hypothalamus, which issues neural and hormonal commands throughout the body to restore estrogen signaling. (5) When the compensatory actions cannot restore estrogen signaling, the breakdown of genomic regulation leads to cancer initiation. (6) Lifestyle factors that upregulate estrogen signaling decrease cancer risk, while downregulating estrogen signaling increases it. Conclusions: Increased cancer risk, insulin resistance, and infertility all originate from defective estrogen signaling.
背景：遗传学研究发现，生殖细胞系BRCA1基因突变是导致癌症风险显著升高的根源。临床研究表明，2型糖尿病患者癌症风险增加可能归因于不健康的生活方式因素和不良习惯。目的：携带BRCA1基因突变或患有2型糖尿病的患者均表现出相似的癌症风险升高、胰岛素抵抗和生育障碍。这表明这三种异常可能源于共同的基因组功能失调，对其机制的解析或可揭示癌症未解之谜。结果：（1）编码雌激素受体α（ERα）、基因组守护蛋白BRCA1和CYP19芳香化酶的ESR1、BRCA1及CYP19基因发生生殖细胞系突变会导致基因组不稳定性。BRCA1和ESR1基因突变特异性引发乳腺癌，而CYP19A基因异常则导致子宫内膜癌、卵巢癌和甲状腺癌。（2）ERα、BRCA1和CYP19芳香化酶蛋白作为转录因子，共同构成由雌激素调控驱动的关键DNA稳定回路。配体激活的ERα通过与多种生长因子协同作用，驱动第二个调控回路以控制细胞增殖。在第三个调控回路中，配体激活的ERα通过与胰岛素、IGF-1及葡萄糖转运蛋白的密切相互作用驱动细胞葡萄糖供应。（3）该三联体中任一转录因子的表达或激活受损都会导致雌激素信号传导缺陷，进而危及正常细胞增殖、胰岛素敏感性和生育功能。（4）由遗传或生活方式因素引起的雌激素信号传导受损会激活下丘脑警报系统，后者通过神经和激素指令调控全身以恢复雌激素信号传导。（5）当代偿机制无法恢复雌激素信号传导时，基因组调控系统的崩溃将引发癌症。（6）上调雌激素信号传导的生活方式因素可降低癌症风险，而下调雌激素信号传导则会增加风险。结论：癌症风险升高、胰岛素抵抗和不孕症均源于雌激素信号传导缺陷。
肿瘤(癌症)患者之家