The tumour suppressor phosphatase PTEN is a key regulator of cellular growth and survival and is among the most frequently mutated genes in human cancers, including breast, endometrial, brain, and prostate cancers. In addition to somatic mutations, germline PTEN mutations give rise to a group of hereditary cancer predisposition disorders collectively known as PTEN Hamartoma Tumour Syndromes (PHTS). PTEN functions primarily by antagonizing the pro-oncogenic PI3K signalling pathway, a central regulator of anabolic processes downstream of receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs).
In the ovary, PTEN plays a critical role in maintaining primordial follicle dormancy, thereby preserving the overall ovarian reserve. Experimental studies have shown that complete loss of PTEN via targeted genomic deletion, results in follicle activation and premature depletion of the follicle pool. However, whether these experimental models accurately reflect the physiological consequences of PTEN mutations in humans remains unknown.
Here, using novel PTEN knock-in mouse models carrying cancer-associated and PHTS germline PTEN mutations, we demonstrate that physiological reductions in PTEN function impair fertility in both male and female mice. These findings provide evidence that reproductive dysfunction may be an underappreciated feature of PHTS patients and provides support for the development of fertility preservation strategies in affected individuals.