Khushi Noorani

Background: Endometrial cancer is one of the most common gynecologic malignancies and develops through progressive molecular alterations that promote uncontrolled cellular growth and survival.¹ Among these alterations, loss of phosphatase and tensin homolog (PTEN) represents one of the earliest and most frequent molecular events identified in endometrial carcinogenesis.^{1, 3} PTEN functions as a tumor suppressor that negatively regulates the PI3K/AKT signaling pathway and maintains cellular proliferation, apoptosis, and genomic stability.^1,3 PTEN loss has been identified not only in established endometrial carcinoma but also within precursor lesions and endometriosis-associated tissue, suggesting an important role in early disease progression.¹ Although PTEN mutation is well established as a common molecular abnormality, the mechanisms through which PTEN loss contributes to malignant transformation and disease progression remain incompletely understood. Understanding these mechanisms may provide insight into prognostic markers and future therapeutic targets.

Objective: This narrative review examined the role of PTEN loss as a central driver of endometrial carcinogenesis and evaluated how PTEN deficiency promotes tumor progression through coordinated effects on proliferative signaling, genomic maintenance, and modulation of the tumor immune microenvironment.

Search Methods: A literature search was conducted using the PubMed database to identify studies published between 2020 and 2025. Search terms included “PTEN,” “endometrial cancer,” “endometriosis,” “PTEN deficiency,” “miR-424(322)~503,” “DNA repair,” “DDB2,” “immune infiltration,” and “tumor microenvironment.” Primary mechanistic studies and clinical outcome studies examining PTEN-associated pathways in endometrial disease were included.

Results: Multiple studies demonstrated that PTEN loss functions as a coordinated regulator of tumor progression through several interconnected mechanisms. Tucker et al. demonstrated that PTEN loss in endometriosis lesions correlated with increased disease burden and greater surgical complexity, suggesting that molecular alterations may precede malignant transformation.¹ Vidal-Sabanés et al. found that PTEN-deficient tumors rely on the miR-424(322)~503 microRNA cluster to sustain proliferation and cellular survival, identifying an important downstream signaling mechanism.² Hameed et al. showed that PTEN-deficient cells exhibited increased DDB2 expression and enhanced nucleotide excision repair activity, allowing tumor cells to tolerate DNA damage and maintain survival despite genotoxic stress.³ Additionally, Tao and Liang reported associations between PTEN mutation status and altered immune cell infiltration patterns, suggesting a role for PTEN in promoting immune escape and shaping the tumor microenvironment.⁴ Clinical findings from population-level studies demonstrated that aggressive disease subtypes and advanced stages were associated with worse survival outcomes.⁵ Together, these findings indicate that PTEN loss contributes to tumor progression through simultaneous enhancement of proliferative signaling, cellular survival, and immune evasion.

Conclusion: PTEN loss represents an early and central event in endometrial carcinogenesis that contributes to disease progression through coordinated enhancement of proliferation, genomic survival, and immune modulation.^1-4 Together, these mechanisms provide a biologically plausible explanation for the aggressive clinical phenotypes observed in endometrial cancer and establish PTEN as a clinically relevant prognostic marker. Future research should investigate targeted therapeutic approaches involving miR-424(322)~503 inhibition, modulation of DNA repair pathways, and immunotherapeutic strategies tailored toward PTEN-associated molecular alterations.^2-4

Works Cited

1. Tucker DR, Lee AF, Orr NL, et al. Somatic PTEN and ARID1A loss and endometriosis disease burden: a longitudinal study. Hum Reprod. 2025;40(2):296–309.
2. Vidal-Sabanés M, Bonifaci N, Navaridas R, et al. Endometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503. Cell Death Dis. 2025;16(1):705.
3. Hameed JSF, Devarajan A, Devu Priya MS, et al. PTEN-negative endometrial cancer cells protect their genome through enhanced DDB2 expression associated with augmented nucleotide excision repair. BMC Cancer. 2023;23(1):399.
4. Tao Y, Liang B. PTEN mutation: A potential prognostic factor associated with immune infiltration in endometrial carcinoma. Pathol Res Pract. 2020;216(10):152943.
5. Kim S, Lee JY, Park HS, et al. Trends in the incidence and survival outcomes of endometrial cancer in Korea: a nationwide study. J Gynecol Oncol. 2024;35(3):e32.