# Human Cancers Derived from Either Genetic or Lifestyle Factors Are Initiated by Impaired Estrogen Signaling

## TL;DR

The paper explains how impaired estrogen signaling, from genetic or lifestyle causes, leads to cancer by disrupting genomic stability and metabolic processes.

## Contribution

It proposes a unified mechanism linking genetic mutations and lifestyle factors to cancer through estrogen signaling disruption.

## Key findings

- Genetic mutations in ESR1, BRCA1, and CYP19A cause genomic instability and specific cancers.
- Impaired estrogen signaling triggers compensatory responses that eventually fail, leading to cancer.
- Lifestyle factors affecting estrogen signaling influence cancer risk.

## Abstract

Impaired estrogen signaling caused by either endogenous or environmental factors alarms the hypothalamus, which then issues neural and hormonal commands throughout the whole body to restore genomic stability. In the first, compensated phase of defective estrogen signaling, patients appear healthy. Hyperinsulinemia is a subtle signal of the genome that indicates successful restoration of estrogen signaling at the expense of excessive insulin synthesis. Over time, the strengthening defect in estrogen signaling and impaired glucose uptake result in metabolic syndrome, with various symptoms and altered laboratory findings. The compensatory molecular changes are warnings from an endangered genome struggling to restore estrogen signaling and DNA stability. The worsening defect in estrogen signaling leads to type-2 diabetes, reflected by increased serum glucose levels despite all compensatory actions, while organs suffer from the lack of glucose and excessive lipid deposition. The complete breakdown of estrogen signaling results in DNA damage and cancer initiation in the affected organ. Cancer development is the genome’s cry for help to combat against dysregulation.

Background: Genetic studies have found that a germline BRCA1 gene 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 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 specifically cause breast cancer, while error in the 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 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.