Human Cancers Deriving from Either Genetic or Lifestyle Factors, Are Initiated by the Damage of Estrogen Signaling

Background. Genetic studies justified that germline BRCA1 gene mutation is the origin of highly increased cancer risk. Clinical studies suggested that increased cancer risk in type-2 diabetes maybe attributed to unhealthy lifestyle factors and bad habits. Purpose. Patients with either BRCA1 gene 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 on ESR1, BRCA1, and CYP19A genes encoding estrogen receptor alpha (ERα), genome safeguarding BRCA1 protein and CYP19 aromatase enzyme, cause genomic instability. BRCA1 and ESR1 gene mutations cause particularly breast cancer, while the error of CYP19A gene 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 for controlling cell proliferation as well, 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. Weakening 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. Weakening estrogen signaling caused by either genetic or lifestyle factor, is alarming for the hypothalamus and it sends neural and hormonal commands throughout the body so as to restoring estrogen signaling. 5. When the compensatory actions cannot restore estrogen guideline, the breakdown of genomic regulation leads to cancer initiation. 6. Lifestyle factors upregulating estrogen signaling, decrease, while downregulating estrogen signaling increases the risk for cancer. Conclusion. Increased cancer risk, insulin resistance and infertility all are originating from defective estrogen signaling.