EMERGING research on breast cancer risk screening suggests that evaluating biological mechanisms and genetic susceptibility before initiating hormone replacement therapy (HRT) may help identify women at higher risk of developing breast cancer. Investigators from the University of Tuebingen, Germany, and Capital Medical University in Beijing, China, explored two biological pathways linked to breast cancer development during HRT, focusing on hormone driven cell proliferation and the formation of potentially genotoxic oestrogen metabolites.
Hormone Driven Proliferation and Biomarker Discovery
One proposed mechanism involves oestrogen induced proliferation of breast cells, which may be further enhanced by certain progestogens. Earlier commentary on major clinical trial findings suggested that differences in breast cancer incidence could be related to overexpression of progesterone receptor membrane component 1 (PGRMC1), a member of the membrane associated progesterone receptor family.
Researchers investigated this pathway through a series of laboratory experiments in breast cancer cell models, followed by animal studies and clinical investigations in patients with breast cancer. Across these studies, circulating levels of PGRMC1 were examined in relation to established clinical features associated with breast cancer risk.
The investigators reported that blood concentrations of PGRMC1 correlated with recognised risk indicators and demonstrated greater predictive potential than traditional tumour markers such as carcinoembryonic antigen, cancer antigen 125, and cancer antigen 15–3. These findings suggest that PGRMC1 may serve as a novel biomarker to support breast cancer risk screening prior to initiating hormone replacement therapy.
Oestrogen Metabolism and Genetic Susceptibility
A second biological mechanism examined in the research involves oestrogen metabolism. While oestradiol is primarily metabolised through pathways producing estrone and estriol, smaller quantities of catechol oestrogens such as 2 hydroxyestradiol and 4 hydroxyestradiol are also generated. These compounds can form carcinogenic quinones if protective enzymatic pathways are impaired.
The authors noted that genetic polymorphisms affecting detoxifying enzyme systems may influence this metabolic balance. Screening for multiple polymorphisms could therefore contribute to breast cancer risk screening before HRT initiation.
Additionally, two case control studies demonstrated that the ratio of 2 hydroxyestradiol to 16 hydroxyestradiol may serve as a predictive marker for breast cancer risk. However, investigators emphasised that oxidative cellular stress appears to be a necessary condition for this pathway to become clinically significant. Environmental exposures such as smoking or industrial pollution may therefore amplify the impact of genotoxic oestrogen metabolites.
Toward Personalised Breast Cancer Risk Assessment
Collectively, these findings highlight the potential for mechanism-based breast cancer risk screening to refine individual risk assessment prior to hormone replacement therapy. The combined evaluation of circulating PGRMC1 levels, metabolic oestrogen profiles, and genetic polymorphisms could support more personalised decision making for clinicians considering HRT.
The researchers suggest that integrating such biomarkers into clinical screening strategies may help identify women who would benefit from closer monitoring or alternative therapeutic approaches.
Reference
Mueck A. Can screening reduce the breast cancer risk induced by HRT? ISGE 3 Meet the Expert. ISGE Annual Congress, 4-6 March, 2026.
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