A Literature Review: The Role of PTEN Gene Expression in the Progression of Endometriosis

Abstract 

This literature review explores the role of PTEN expression in the progression of endometriosis, focusing on its impact on the cell cycle, the severity of endometriosis, and the rate of apoptosis and autophagy. Drawing on recent studies from 2009 to 2024, this review explores the underlying cellular mechanisms behind endometriosis progression concerning PTEN expression. Findings indicate that loss of PTEN gene expression leads to increased cell division, more severe forms of endometriosis, and reduced control over apoptosis and autophagy. Further research, however, is necessary to explore the complex interplay between gene expression that leads to endometriosis. 

The Role of PTEN Gene Expression in the Progression of Endometriosis

Endometriosis is a gynecological disorder involving abnormal endometrial growth outside of the uterus. The endometrium, also called the “innermost lining of the uterus”, typically develops during puberty but regenerates every menstrual cycle in response to steroid hormones estrogen and progesterone (Mirzaei, et al., 2021, p.45). Although endometriosis affects 10 to 15% of the female population worldwide, its exact cause remains unknown (Chycezewski et al., 2009). Endometriosis can be characterized by abnormal growth of tissues, invasion of other organs, and bleeding outside the uterus, affecting the quality of life of many women worldwide. However, currently available treatments have side effects like liver damage, weight gain, gastrointestinal discomfort, and menopause-like symptoms. Hence, research dedicated to determining the cause of endometriosis is critical in improving the diagnosis and treatment of this benign yet debilitating condition. One of the key limitations in current endometriosis research is the fact that endometriosis can only be diagnosed via invasive methods, such as a laparoscopy or laparotomy, leading to fewer diagnoses in areas without access to proper medical technologies and assistance. 

Phosphatase and Tensin Homolog, often referred to as PTEN, is a type of tumor suppressor gene that regulates the cell cycle comprised of nine exons and 403 amino acids on chromosome 10q23.3 (Jia et al., 2016). Loss-of-function mutations in PTEN have been reported in around 14 to 18% of endometriosis cases, with the most common mutations being nonsense mutations (where there is a premature stop codon in the nucleotide sequence), frameshift (the insertion or deletion of nucleotides that lead to a change in the reading frame of the mRNA), missense (a nucleotide sequence change that results in coding for a different amino acid than the normal amino acid), and deletion mutation (a deletion of a single nucleotide), along with epigenetic changes (Allaire, et al., 2025). 

PTEN has two significant roles during the cell cycle, including regulating the transition from G1 to S and G2 to M phases. First, during the G1 phase, cells typically grow, obtain resources from the environment, and prepare for DNA replication in the S phase. Cells can pass through this phase by activating G1 cyclin-dependent kinase and cyclin complexes, including CDK 4/6 with the D-type cyclin and CDK2 with the E-type cyclin. The activated D-CDK4/6 complex then phosphorylates the retinoblastoma protein (RB), which causes the histone deacetylase 1 (HDAC1) and transcription factor E2F-1 to detach from RB, thereby activating the genes downstream, which include cyclin E, that then attaches to CDK2 to form another complex. PTEN, located in the nucleus and cytoplasm, works by catalyzing the reaction that converts phosphatidylinositol-3, 4, 5-triphosphate (PIP3) into phosphatidylinositol-4, 5-bisphosphate (PIP2), which results in decreased cell growth and survival. PTEN inhibits the PI3K/AKT pathway, preventing the activation of cyclin-CDK complexes necessary for cells to enter the S phase, effectively halting the development of uncontrolled cell division. In the meantime, PTEN also controls the cell cycle in the G2-M transition, where cells prepare to divide in mitosis by being involved in many checkpoints requiring DNA replication to be completed successfully before division. In mitosis, PTEN facilitates the structure and binding of the mitotic spindle to the chromosomes, ensuring that an equal number of chromosomes are distributed to each daughter cell. 

This literature review examines the relationship between the PTEN tumor suppressor gene and endometriosis, contending that the presence or absence of loss-of-function mutations in the PTEN gene will impact the severity of endometriosis. While many different types of genes are involved in endometriosis-like symptoms, this review focuses on the presence of the PTEN gene in cell cycle progression, the severity of endometriosis, and the rate of apoptosis and autophagy. 

Review

It is known that the PTEN gene controls the PI3K/AKT signaling pathway, thereby negatively regulating angiogenesis and vascular endothelial growth factor (VEGF), both of which are key processes necessary for the growth and division of cells. Many previous studies have also observed a high frequency of loss of heterozygosity (LOH) in the PTEN gene in patients with ectopic endometriosis as a result of a structural frameshift and insertion mutation at the N-terminal phosphatase region of PTEN. A study by Jia et al. (2016) aimed to isolate the role of PTEN in endometriosis in primary human endometrial cells and human-mouse chimeric endometriosis animal models, and more specifically, examine how the expression of PTEN affects the cell cycle of the primary endometrial cells after PTEN transfection and how re-initiating the PTEN expression may impact cell apoptosis, angiogenesis, and VEGF expression of endometriosis in the animal model. 

To first identify the role of the PTEN gene on human primary endometrial cells, the study first synthesized and cloned the PTEN gene into pLV-IRES-PURO Plasmid. Short-hairpin RNA (shRNA)---or RNA used to prevent gene expression through a process known as RNA interference—was synthesized and inserted into pLV-2shPTEN and pLV2-shNC vectors, which carry these foreign genes into 293T cell-packed lentivirus. Ultimately, the lentivirus was used to infect the endometrial cells in vitro. The study used five groups and performed gene knockout to identify the effect of different environmental conditions on PTEN gene expression. The five groups include a blank group (used as a control), a vector group (transfected with pLV-PTEN, acting as the negative control to the over-PTEN group), an over-PTEN group (transfected with pLV-PTEN), a siNC group (a negative control to the siPTEN group), and the siPTEN group. Then, after each group was washed and centrifuged, the study used a Western blot analysis to identify patterns in the cell cycle. 

The study's results supported their initial hypothesis that PTEN expression influences cell division in primary human endometrial cells. The study found that PTEN overexpression significantly increased the levels of apoptosis of endometrial cells. In contrast, low levels of PTEN expression were associated with higher levels of angiogenesis, or the growth of new capillaries, which may support tumor growth. 

The journal also discovered how the overexpression of PTEN resulted in a greater proportion of cells in the G0/G1 phase, where cells are non-dividing or not yet in mitosis, while fewer cells were present in the G2/M phase, indicating that the cell cycle was arrested at the G0/G1 phase when PTEN was overexpressed. This result suggests that a loss-of-function mutation of the PTEN gene may induce increased cell division, forming an endometrial lesion or any abnormal change to an organ. 

In the meantime, to isolate the role of the PTEN gene in endometriosis in animal cells, the study utilized cells from 18 female severe combined immunodeficiency (SCID) mice that were provided with food, water, and shelter and randomly selected to be studied. Their endometrial samples were then pre-cooled, washed, and centrifuged. The study quantified PTEN expression in animal models through the presence or absence of brown granules in the cytoplasm and the nucleus. The researchers then used a score ranging from 0 to 3 to categorize the level of PTEN expression; a score of 0 signified no PTEN expression, a score of 1 signified 1-25% of cells with PTEN expression, a score of 2 signified 26–49% of cells with PTEN expression, and a score of 3 signified >50% cells with PTEN expression. The study also considered the intensity of the brown color to truly identify whether the difference between the control and experimental groups was significant. 

Eventually, Jia et al. found that the percentage of PTEN-positive cells, or those that displayed brown granules, was significantly greater in the over-PTEN group than in the control and si-PTEN groups. The VEGF-positive cells, however, were greater in the si-PTEN group than in the control and over-PTEN groups, confirming the general theory that PTEN is responsible for negatively regulating the expression of VEGF. 

While the results of this study display how angiogenesis and the expression of VEGF are critical to providing the energy and resources necessary for mutated/abnormal tissues to survive and continue proliferating, they do not yet guarantee that re-introduction of the expression of the PTEN gene in patients will lead to positive clinical outcomes. Hence, this may suggest that PTEN has a multifaceted role in preventing ectopic tissue growth by regulating angiogenesis, apoptosis, and cell cycle checkpoints. 

Building on these findings,  Allaire et al. (2025) observed patterns of PTEN somatic loss in individuals at different stages of endometriosis, categorizing individuals as having SUP (superficial peritoneal endometriosis), DE (deep endometriosis), and OMA (ovarian endometrioma). DE and OMA were considered the "severe" anatomic subtypes of endometriosis. In contrast, SUP was classified as the "mild" anatomic subtype to test the hypothesis that somatic PTEN loss is more common in patients with severe types of endometriosis (DE and OMA) than in those with mild forms (SUP). 

This longitudinal study was conducted from 2013 to 2017 at the BC Women's Center for Pelvic Pain and Endometriosis. It used immunohistochemistry staining to identify the presence of the loss of PTEN gene expression in the cytoplasm of endometrial cells. The IHC scoring had four primary categories to identify whether there was a loss of PTEN expression in patients with the categories ranging from 0% loss in epithelial cells, 1-10% loss, 11-49% loss, and 50-100% loss. This study only considered loss in the expression of the PTEN gene of a patient with endometriosis if there were at least 10 nearby endometriosis epithelial cells with the PTEN loss. 

Allaire et al. used endometriosis patients' anatomic subtypes, the rARSM scale (I-IV)—a scale used to determine the severity of endometriosis—, and patient outcome (quantified via pain score and surgical difficulty) to identify whether there is an actual correlation between the PTEN gene expression and endometriosis severity and outcome. 

While the study did not specifically identify what mutation in the PTEN gene led to the loss of expression of the PTEN, the study ascertained that PTEN somatic loss is present more frequently in severe anatomic subtypes and higher stages of endometriosis with around 72.7% of participants with DE or OMA (either but not both conditions) having PTEN loss. In contrast, only 46.4% of the SUP patients had PTEn somatic loss. Moreover, 81% of individuals with Stage IV endometriosis had a somatic loss of PTEN expression, whereas only 47.8% of individuals with Stage I endometriosis did not express PTEN. Indeed, it is difficult to determine whether this correlation can also be considered a cause-and-effect relationship; however, these findings display how a loss-of-function mutation of the PTEN tumor suppressor gene may be responsible for severe conditions associated with endometriosis. Also, other genes may be involved in the presence or absence of endometriosis, including ARID1A, suggesting further research in this area.

As a result of this association between PTEN loss and severity of endometriosis, this could lead to greater disease burden and difficulties during surgery. This study found that PTEN loss was correlated with longer surgical times in non-white ethnicity/race demographics. However, non-white ethnicity/race groups also had greater pain levels and scored higher on the rARSM scale, indicating that factors other than PTEN loss may have contributed to this result. In general, however, the study did not find any association between PTEN loss and post-operation pain level or the frequency of reoperation. 

Although the previous two studies primarily focused on the role of PTEN expression on the cell cycle and endometriosis severity, Choi et al. (2017) studied how PTEN affects the PI3K/AKT/mTOR pathway to change levels of apoptosis and autophagy. Apoptosis is a type of programmed cell death (PCD), and reduced apoptosis in endometrial cells has been associated with increased survival of endometrial cells in abnormal locations of the body, potentially causing the symptoms of endometriosis. Autophagy is another type of PCD, where autophagosomes—areas of cytoplasm enclosed in double membranes—mature and combine with lysosomes to be degraded. Previous hypotheses believed that autophagy was an evolutionary mechanism that resulted from a response to a lack of nutrients or resources in an environment for the survival of organisms. However, autophagy has also been shown to play a significant role in the development of endometriosis, since mTOR, a negative regulator of autophagy, is de-repressed in endometriosis, leading to decreased autophagy and apoptosis. As a result, PTEN has been speculated to be involved in the negative regulation of the mTOR pathway. However, based on the limited research on the effect of the PTEN gene expression on the regulation of autophagy, Choi et al. exposed endometrial cells to progesterone, a hormone produced in the ovaries, to identify how a lack of PTEN gene expression affects apoptosis and autophagy. This study initially hypothesized that the percentage of cells in apoptosis and autophagy in normal endometrial cells would increase in the presence of progesterone. 

To start, the study collected normal endometrial stromal cells (NESCs) and endometriotic cyst stromal cells (ECScs), rinsed them with PBS to eliminate unwanted debris, and cultured them with 1 mL of culture medium. (Stromal cells are tissue cells that connect other tissues and organs.) 

All NESC and ECSC groups were treated with sex steroids, oestradiol, or progesterone, for 72 hours and pre-cultured in a serum-free Earle's Balanced Salt Solution (EBSS) medium. Then, some groups of cells were exposed to PTEN and progesterone inhibitor treatments so that the researchers could observe the effect of blocking progesterone on apoptosis and autophagy. Ultimately, by using a Western blot technique, the researchers determined AKT activity by identifying the number of phosphorylated (activated) AKT, mTOR pathway activity by finding the number of phosphorylated ribosomal protein S6 kinase (S6K), which is a substrate in this pathway, and endometrial cell apoptosis rate by evaluating the number of cleaved poly ADP-ribose polymerase (PARP) and cleaved caspase-3. This study used immunofluorescence to identify each of the factors involved in these pathways, along with transmission electron microscopy to assess whether the level of AKT activity, mTOR pathway, and apoptosis rate in the NESCs significantly differed from that of the ECSCs. 

  The study found, as expected, that the estrogen-treated NESCs in the presence of progesterone had increased levels of PTEN and decreased AKT and S6K levels. Yet, after using the progesterone and PTEN inhibitors, PTEN expression decreased, and AKT and S6K phosphorylation decreased. 

This study, however, did not solely want to confirm the theory that PTEN expression leads to increased apoptosis. Hence, researchers went a step further by evaluating whether PTEN-mediated autophagy stimulated apoptosis in NESCs. Results showed that the progesterone-treated NESCs had increased levels of cleaved PARP and cleaved caspase-3 compared to those of the estrogen-treated NESCs, displaying how apoptosis increased by around 2.23-fold when progesterone was present. Finally, when the amount of phosphorylated AKT and S6K was measured in estrogen-treated and progesterone-treated NESCs, the study found that the removal of both steroids led to significantly higher levels of PTEN expression and decreased levels of phosphorylated AKT and S6K expression, providing insight into how PTEN regulates these proteins in the presence of steroid hormones. 

This study determined that steroid hormones increase PTEN expression, which regulates the AKT/mTOR signaling pathway in normal endometrial stromal cells, leading to autophagy, which, in turn, leads to increased apoptosis. On the other hand, endometriosis stromal cells do not adequately respond to progesterone, which decreases PTEN expression, preventing the inhibition of the AKT/mTOR pathway, and leading to decreased apoptosis. 

At the end of the day, endometriosis continues to be an obscure medical condition. Previous studies have found that endometriosis may have a genetic basis, with Simpson et al. discovering in 1980 that individuals with endometriosis had 5.9% of mothers and 8.1% of sisters with endometriosis as well; on the other hand, individuals without endometriosis had a significantly lower percentage of mothers and sisters with endometriosis. Additionally, patients with endometriosis in families with endometriosis also tend to display more severe symptoms of endometriosis, posing the question of whether endometriosis can be inherited across generations as well. 

Cardon et al. (2004) hypothesized that endometriosis may display familial clustering—or the chance that a disease or trait might appear more frequently in members of the same family than by random chance alone—and used a large rhesus monkey population to identify whether this pattern was valid. The study found that monkeys have a higher risk of being affected by endometriosis if they are closely related to other female monkeys currently affected by endometriosis, indicating that endometriosis may have a hereditary basis. 

Conclusions

In overview, tumor suppressor genes like PTEN often play significant roles in various biological pathways, including pathways that control apoptosis, cell division, and the progression of endometriosis. From the studies reviewed, PTEN expression is critical in limiting excess cell division or creation by regulating the PI3K/AKT/mTOR pathway. Loss-of-function mutations in the PTEN gene, however, may lead to the formation of ectopic cysts and more severe stages of endometriosis, leading to greater surgery difficulty or increased pain levels. As a result, a deeper understanding of the cellular mechanism that drives endometriosis and identifying the genes involved in this condition can lead to the establishment of more effective diagnostic tools and treatments in the future.

References

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Cover photo via PTEN Research

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Originally published at themedtales.com