Impact of Breast Cancer on Ovarian Function: Dysregulation of Cholesterol Homeostasis in Cumulus Cells and Follicular Fluid

Background/Objectives: Women undergoing fertility preservation by oocyte vitrification before oncological treatments often have a poorer ovarian response to stimulation than healthy women. This indicates that cancer itself can adversely affect ovarian function. However, this impact remains unclear, and its underlying mechanisms are poorly understood. We investigated in this study whether breast cancer, the most common form of cancer in women of reproductive age, alters ovarian function by itself. Methods: For this purpose, we compared the ovarian response to hormonal stimulation in women with breast cancer undergoing oocyte cryopreservation with that in oocyte donors, adjusting for age and BMI. We analysed our data according to the molecular subtype of breast cancer, tumour grade, lymph node invasion, and BRCA1 mutation status. Secondly, we evaluated whether breast cancer alters cholesterol homeostasis in cumulus cells, given its essential role in oocyte quality. The expression of genes involved in cholesterol biosynthesis was analysed in cumulus cells using RT-qPCR, while the concentrations of cholesterol and its intermediates were quantified in follicular fluid using GC-FID and GC-MS/SIM. Results: Compared with oocyte donors, breast cancer patients exhibited a significant decrease in collected oocytes after stimulation. At the molecular level, our data revealed a significant deregulation of cholesterol biosynthesis gene expression in cumulus cells of women with breast cancer. The quantification of cholesterol and its intermediates in follicular fluid revealed altered concentrations in women with breast cancer, suggesting a disrupted follicular microenvironment. Conclusions: These findings suggest that breast cancer impairs ovarian function, at least in part, by disrupting cholesterol homeostasis, which can lead to reduced oocyte competence.