A preclinical mouse model mimicking the ovarian cancer-induced estrogen deficiency-depression axis

Young ovarian cancer (OC) patients often experience a synergistic interplay among tumor progression, estrogen deficiency, and depression, which severely compromises prognosis and quality of life. However, a preclinical model that faithfully recapitulates this triad remains lacking. This study aimed to develop and validate a novel mouse model to investigate the interrelationship between ovarian cancer, hypoestrogenic states, and depression.

An ovarian cancer-related depression (OCRD) model was established by integrating previously validated components of tumor-depression paradigms, including ID-8 ovarian cancer modeling and chronic restraint stress-induced depressive-like behavior. Orthotopic (intraperitoneal) and heterotopic (subcutaneous) tumor models were combined with chronic stress. Estrogen status was manipulated by ovary retention or ovariectomy (OVX), performed either 1 day before tumor implantation to model preexisting estrogen deficiency or 7 days after engraftment to mimic treatment-induced abrupt hormonal loss. Model validity was assessed using behavioral assays (sucrose preference test, tail suspension test, and open field test), neuroendocrine profiling, and longitudinal evaluation of tumor progression.

The model generated by intraperitoneal tumor engraftment, OVX, and chronic stress exhibited pronounced depressive-like behavior, accompanied by marked estrogen depletion and accelerated tumor progression. All mice survived throughout the experimental period, indicating high model stability and reproducibility. This integrated phenotype closely mirrors key clinical features observed in young OC patients undergoing abrupt estrogen deprivation.

The combination of intraperitoneal ovarian cancer modeling, ovariectomy, and chronic stress induction establishes a stable and clinically relevant preclinical model of hypoestrogenic ovarian cancer-related depression, suitable for translational research.