Ovarian microcystic stromal tumor is exceptionally rare. Since it was first delineated as a distinct entity, only a limited number of cases have been documented in the medical literature worldwide. The tumor belongs to the broad family of ovarian stromal neoplasms, which arise from the supportive tissue of the ovary rather than from the egg cells themselves. What distinguishes MCST is its striking microscopic appearance: the tumor is composed of sheets and nests of relatively uniform cells arranged around a network of tiny, fluid-filled microcysts that give the lesion its name. Under the microscope, this architecture can resemble other ovarian tumors, including yolk sac tumor or even certain metastatic cancers, which historically made diagnosis challenging.

The key to recognizing MCST lies in its immunohistochemical fingerprint. Tumor cells in these lesions characteristically show nuclear expression of β-catenin, a protein that serves as a hallmark feature and helps separate MCST from its many microscopic mimics. The tumors also typically express Cyclin D1, CD10, vimentin, WT1, FOXL2, and SF1, a constellation of markers that pathologists use to confirm the diagnosis and to exclude other possibilities. Despite this growing list of identifying features, the biological behavior and molecular underpinnings of MCST remain incompletely characterized, largely because so few cases exist to study. Most reported tumors have behaved in a benign fashion, and conservative surgical management has generally proven sufficient.

The newly reported case involved a 38-year-old woman who had never been pregnant and who carried a history of irregular menstruation. Her ovarian mass was discovered incidentally, meaning it was found without the patient having shown symptoms directly attributable to the tumor. An initial intraoperative frozen-section examination pointed to a benign sex cord-stromal tumor, allowing the surgical team to proceed with a laparoscopic tumor enucleation, a fertility-sparing approach in which the tumor is shelled out while the ovary is preserved. This minimally invasive strategy reflects the growing recognition that, in carefully selected patients with apparently benign ovarian lesions, organ-preserving surgery can offer excellent outcomes without the need for more radical procedures.

Definitive histopathological examination confirmed the diagnosis of microcystic stromal tumor. The tumor displayed the characteristic morphology and the expected immunoprofile, with positivity for β-catenin, Cyclin D1, CD10, vimentin, WT1, FOXL2, and SF1. But two findings set this case apart. First, the tumor cells showed partial positivity for S100, a calcium-binding protein commonly expressed in neural, melanocytic, and certain other tissues, and one that is not typically associated with MCST. Second, and perhaps more strikingly, the tumor exhibited what the authors describe as a distinctive hormone receptor signature: androgen receptor was strongly expressed in approximately 90 percent of tumor cell nuclei, while progesterone receptor was weak, present in only about 15 percent of cells.

Androgen receptor expression in ovarian tumors carries particular interest because the androgen receptor participates in signaling pathways relevant to ovarian physiology and ovarian carcinogenesis. Its strong expression in this MCST raises questions about whether hormone signaling might play a role in the growth or regulation of these tumors, or whether the finding represents an incidental epiphenomenon without clinical consequence. Similarly, S100 expression introduces a diagnostic wrinkle: S100 positivity can suggest alternative diagnoses, including neural tumors or melanocytic lesions, and its partial presence in an otherwise classic MCST underscores the importance of interpreting immunohistochemical panels in context rather than relying on any single marker. Although androgen receptor expression has been reported in MCST before, and focal S100 positivity has been documented in at least one prior case, the co-existence of both features in a single tumor has only rarely been recorded.

The clinical course of the patient adds a reassuring dimension to the report. Following her laparoscopic enucleation, she recovered well, and follow-up at 28 months revealed no evidence of recurrence. This outcome is consistent with the prevailing understanding of MCST as a typically indolent neoplasm, and it supports the feasibility of conservative surgery combined with careful long-term surveillance in affected patients. For a young woman whose tumor was detected before any malignant transformation or complication, the preservation of ovarian tissue represents a meaningful quality-of-life benefit, and the extended recurrence-free follow-up provides additional confidence in the benign trajectory of this tumor type.

The authors of the report paired their case with a review of the existing literature, aiming to consolidate what is known about the clinicopathological features of MCST and its unusual immunophenotypic variants. Because the entity is so rare, individual case reports effectively serve as the primary source of knowledge, each one contributing data points that slowly refine the diagnostic criteria and the understanding of biological behavior. The review situates the present case within this accumulating record, noting both the consistency of core features—microcystic architecture, nuclear β-catenin, and benign behavior—and the variability in secondary findings such as hormone receptor status and unexpected marker expression.

The report also highlights the practical implications for diagnostic pathology. Pathologists confronting an ovarian microcystic lesion must distinguish MCST from a differential diagnosis that includes yolk sac tumor, juvenile granulosa cell tumor, and clear cell carcinoma, among others. Unusual immunostaining results, such as partial S100 positivity, could easily send the diagnostic workup down an erroneous path if not weighed against the full morphological and immunophenotypic picture. Cases like this one, in which atypical marker expression arises within an otherwise typical tumor, help calibrate the diagnostic thresholds that practicing pathologists apply, reducing the risk of both overdiagnosis and missed diagnosis.

For now, the biological significance of the combined androgen receptor and S100 expression observed in this tumor remains unresolved. The authors emphasize that larger case series will be needed to determine whether such immunophenotypic variation carries any prognostic or therapeutic relevance, or whether it simply reflects the natural heterogeneity of a rare neoplasm. In the meantime, the case stands as a reminder of how much remains to be learned about even the quietest corners of tumor biology—and of how a single carefully documented patient can meaningfully advance the field. The 28-month disease-free outcome offers comfort to patients facing similar diagnoses, while the unusual molecular profile offers scientists a fresh line of inquiry into the mechanisms that drive this enigmatic ovarian tumor.

Subject of Research: A rare benign ovarian stromal neoplasm exhibiting an atypical immunophenotype with androgen receptor and partial S100 expression

Article Title: Ovarian microcystic stromal tumor with unusual expression of AR and partial S100: a case report and literature review

Article References: Liu, M., Sun, Y., Yin, J., Liu, K., & Jiang, Z. (2026). Ovarian microcystic stromal tumor with unusual expression of AR and partial S100: a case report and literature review. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02276-7

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02276-7

Keywords: ovarian tumor, microcystic stromal tumor, MCST, androgen receptor, S100, β-catenin, immunohistochemistry, sex cord-stromal tumor, case report, ovarian pathology, laparoscopic surgery, Journal of Ovarian Research

Hepatocellular carcinoma, or HCC, is one of the leading causes of cancer-related death worldwide, and its molecular landscape has been mapped in increasing detail over the past decade through large-scale sequencing efforts. Among the recurrent alterations identified in human HCC samples, mutations in CTNNB1 and in the TERT promoter stand out for their exceptionally high frequency. CTNNB1 mutations stabilize the β-catenin protein, allowing it to escape degradation, accumulate in the cell nucleus and drive the expression of proliferation-promoting genes. TERT promoter mutations, meanwhile, create binding sites for transcription factors that boost expression of telomerase reverse transcriptase, the enzyme that rebuilds chromosome ends and grants cells the replicative immortality that cancer demands. Despite the well-documented prevalence of both alterations, the functional consequences of their co-occurrence had remained poorly understood, leaving a significant gap in the mechanistic picture of how liver tumors arise.

To begin closing that gap, the research team first turned to publicly available data from The Cancer Genome Atlas, or TCGA, a comprehensive genomic database of human tumors. Their statistical analysis of HCC samples revealed a significant association between mutations in CTNNB1 and mutations in the TERT promoter, with a Fisher’s exact test yielding a P value below 0.01. In practical terms, this means that liver tumors carrying one of these alterations are significantly more likely than chance alone would predict to carry the other as well. Such non-random co-occurrence is a classic signature of cooperating cancer genes: when two alterations appear together more often than expected, it typically suggests that their combined effect confers a selective growth advantage that natural selection within the tumor favors strongly.

Association, however, is not causation. To test whether β-catenin and TERT genuinely cooperate in driving liver cancer, the researchers employed an elegant and rapid animal modeling technique known as hydrodynamic tail vein injection, or HTVI. This method involves injecting plasmid DNA into the bloodstream of mice in a way that delivers the genetic material directly into hepatocytes, the main functional cells of the liver, allowing researchers to express specific oncogenes in liver tissue and monitor tumor development over time. The team constructed plasmids encoding a constitutively active form of β-catenin, called Δ90 β-catenin, which carries a deletion that prevents its degradation, alongside plasmids encoding TERT itself.

The results of these experiments were striking. When Δ90 β-catenin and TERT were coexpressed in mouse livers, the animals developed hepatocellular carcinoma rapidly, with tumors emerging far sooner and more abundantly than in any of the control conditions. In contrast, expression of Δ90 β-catenin alone produced only minimal tumor formation, and expression of TERT alone produced essentially no tumors at all. This pattern is the hallmark of oncogenic synergy: neither alteration is sufficient on its own to transform liver tissue, but together they unleash a potent cancer-driving program. The finding provides a functional explanation for the genetic co-occurrence observed in human patient data, and it suggests that the two mutations are not merely passengers traveling together but active collaborators in hepatocarcinogenesis.

With the synergy established, the researchers turned their attention to the molecular mechanism underlying it. Using immunohistochemistry, a technique that detects specific proteins in tissue sections, they examined the tumors induced by combined β-catenin and TERT expression and looked for signs of activated signaling cascades. What they found was strong phosphorylation of ERK1/2, the terminal kinases of the MAPK/ERK pathway, a central signaling cascade that transmits growth-promoting signals from the cell surface to the nucleus. ERK1/2 phosphorylation is a well-established readout of MAPK/ERK pathway activation, and its robust presence in the β-catenin and TERT-driven tumors indicated that this pathway had been switched on in the tumor cells.

To determine whether this pathway activation was merely a byproduct of tumorigenesis or an essential driver of it, the researchers performed a genetic knockdown experiment targeting MEK1/2, the upstream kinases responsible for phosphorylating ERK1/2. When MEK1/2 expression was suppressed in the mouse livers receiving the β-catenin and TERT plasmids, tumor formation was markedly reduced. This loss-of-function experiment confirmed that MAPK/ERK signaling is not incidental but indispensable for the oncogenic cooperation between β-catenin and TERT. In other words, without the MAPK/ERK cascade, the two cancer genes lose their combined power to transform liver tissue, identifying the pathway as a critical dependency of this tumor subtype.

The clinical implications of these findings are considerable. The MAPK/ERK pathway is already a major focus of drug development across many cancer types, and a range of inhibitors targeting components of the cascade, including MEK inhibitors, have been developed and tested clinically. The new study suggests that patients whose liver tumors harbor both CTNNB1 and TERT promoter mutations may represent a molecular subtype that is particularly dependent on MAPK/ERK signaling, and therefore potentially responsive to therapies that target this cascade. Genomic testing for the co-occurrence of these two mutations could, in principle, help identify patients most likely to benefit from such an approach, although the researchers emphasize that their work is preclinical and that translating the findings into patient treatment will require further study.

Beyond its therapeutic implications, the study fills an important conceptual void in liver cancer biology. β-catenin is classically understood as a transcriptional co-activator in the Wnt signaling pathway, and TERT as a guardian of chromosome integrity, so the demonstration that their cooperation routes through MAPK/ERK activation reveals an unexpected layer of crosstalk between these canonical systems. The work was supported by grants from the National Research Foundation of Korea and approved by the Animal Policy and Welfare Committee of Kyung Hee University. As sequencing of liver tumors becomes increasingly routine in clinical practice, mechanistic studies like this one, which connect specific mutation combinations to druggable signaling dependencies, will become ever more essential to realizing the promise of precision oncology in hepatocellular carcinoma.

Subject of Research: Cooperation between TERT promoter mutations and β-catenin activation in hepatocellular carcinoma development via MAPK/ERK signaling

Article Title: Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation

Article References: Park, H., Lee, J., Moon, H., & Ro, S. W. (2026). Telomerase reverse transcriptase (TERT) accelerates β-catenin-driven hepatocarcinogenesis via MAPK/ERK pathway activation. Cancer Cell International. https://doi.org/10.1186/s12935-026-04329-9

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04329-9

Keywords: TERT promoter, β-catenin, hepatocellular carcinoma, MAPK/ERK pathway, liver cancer, telomerase, CTNNB1, oncogenic synergy, hydrodynamic tail vein injection, ERK1/2 phosphorylation, MEK1/2, cancer genetics

In a study published in the journal Molecular Diversity, Kader Sahin of Bahçeşehir University and Bandırma Onyedi Eylül University, Ajda Coker of Marmara University, and Serdar Durdağı of Bahçeşehir University describe a structure-based virtual screening campaign that combed through FDA-approved drugs in search of molecules capable of disrupting the interaction between β-catenin and T-cell factor 4, or Tcf4. This protein–protein interaction is the final, decisive step in Wnt signaling: when β-catenin accumulates in the cell nucleus and binds Tcf4, the complex switches on a battery of genes that drive tumor growth, survival, metastasis, and drug resistance. Block that binding, the logic goes, and the entire oncogenic program collapses.

The catch has always been the shape of the target. The β-catenin/Tcf4 interface sprawls across roughly 4,800 square angstroms, a vast and shallow surface with few of the deep, well-defined pockets that medicinal chemists traditionally exploit. For years, interfaces like this one were written off as undruggable. Yet structural biology has gradually revealed that even sprawling protein–protein interfaces concentrate their binding energy in a handful of so-called hot spots, short stretches of residues that contribute disproportionately to the affinity between the two partners. If a small molecule can be steered into those hot spots, the reasoning goes, it might achieve with a compact drug what would otherwise require a much larger molecule.

That is precisely the strategy the researchers pursued. Rather than screening synthetic chemical libraries filled with untested compounds, they turned to drug repurposing, focusing on medicines that have already passed safety scrutiny and are in clinical use. Repurposing offers a practical shortcut: known pharmacology, established safety profiles, and in many cases existing manufacturing and distribution infrastructure. The team first mapped the critical hot spot residues of β-catenin that engage Tcf4, then used molecular docking to position each candidate drug within the interface, asking which approved molecules could physically occupy and destabilize the contact points that hold the complex together.

The computational pipeline did not stop at docking. To separate plausible binders from artifacts, the researchers subjected the top candidates to physics-based molecular dynamics simulations, watching in atomic detail how each ligand behaved over time when bound to β-catenin. They then calculated binding free energies using the MM/GBSA method, a hybrid approach that combines molecular mechanics energies with implicit solvent models to estimate how strongly a ligand clings to its target. This layered filtering, docking followed by simulation followed by energetic scoring, is designed to weed out compounds that look good in a single static snapshot but fall apart under the thermal motion of a real cellular environment.

Three candidates emerged from the screen with stable binding to the critical hot spot residues of β-catenin, specifically asparagine 430, lysine 435, histidine 470, arginine 474, and lysine 508. They were Leucovorin, also known as folinic acid, a vitamin derivative routinely used to enhance chemotherapy; Carbenicillin, a penicillin-class antibiotic; and Ceforanide, a second-generation cephalosporin. All three are approved, well-characterized medicines, which means that if any of them proves effective against Wnt-driven cancers, the path from bench to bedside could be considerably shorter than for a brand-new chemical entity.

Computational predictions, however convincing, mean little until they are tested in living cells. The team moved their three hits into the laboratory, using HT-29 colorectal cancer cells, a widely studied cell line in which Wnt signaling is aberrantly active. The cells were treated with each compound and assessed for viability and for their ability to form colonies, a measure of long-term proliferative capacity that often correlates with tumorigenic potential. The results were striking: Carbenicillin and Ceforanide reduced cell viability and impaired colony formation, exhibiting superior anti-proliferative activity compared with the other candidates, including Leucovorin.

The convergence between the computational and experimental arms of the study is what gives the findings their weight. The two antibiotics that performed best in cell assays were the same molecules whose simulated binding poses anchored them most securely to the β-catenin hot spots. This consistency suggests that the anti-proliferative effects observed in HT-29 cells may indeed arise from disruption of the β-catenin/Tcf4 interaction, although the researchers are careful to frame the work as a proof of concept rather than a finished therapy. Further studies will be needed to confirm the mechanism directly, to characterize selectivity for cancer cells over healthy tissue, and to establish whether the compounds can achieve therapeutic concentrations in tumors.

Even so, the implications are considerable. Wnt/β-catenin signaling is implicated not only in colorectal cancer but in a broad family of malignancies, including hepatocellular carcinoma and other Wnt-driven tumors, and it also maintains cancer stem cell populations that fuel relapse and metastasis. A validated small-molecule inhibitor of the β-catenin/Tcf4 interaction would be a genuinely new class of anticancer agent, one that attacks the transcriptional engine of the tumor rather than a single downstream symptom. Prior efforts, including peptide mimetics and dedicated small molecules developed in academic labs, have struggled to reach the clinic, which makes the repurposing angle particularly attractive: these are drugs whose toxicity, metabolism, and drug interactions are already documented.

The study also offers a template for tackling other supposedly undruggable targets. By combining hot spot analysis, docking against a library of approved drugs, rigorous molecular dynamics validation, and energetic scoring, and only then moving to cell-based experiments, the researchers demonstrated a workflow that is both computationally disciplined and experimentally grounded. As the authors conclude, their findings provide compelling evidence that targeting the β-catenin/Tcf4 interaction with small molecules is feasible, and that Carbenicillin and Ceforanide may serve as promising repurposed candidates for therapeutic intervention in Wnt-driven malignancies. For patients with colorectal cancer, whose treatment options too often narrow as the disease progresses, the idea that answers might be hiding in plain sight among existing medicines is a hopeful one, and this study shows exactly how such hidden answers can be systematically found.

Subject of Research: Virtual drug repurposing to discover β-catenin/Tcf4 interaction inhibitors for colorectal cancer treatment

Article Title: Hot spot-driven discovery of β-catenin/Tcf4 interaction inhibitors via virtual drug repurposing study and experimental validation in colorectal cancer cells

Article References: Sahin, K., Coker, A., & Durdağı, S. (2026). Hot spot-driven discovery of β-catenin/Tcf4 interaction inhibitors via virtual drug repurposing study and experimental validation in colorectal cancer cells. Molecular Diversity. https://doi.org/10.1007/s11030-026-11720-1

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11720-1

Keywords: β-catenin, Tcf4, Wnt signaling, colorectal cancer, drug repurposing, virtual screening, molecular docking, molecular dynamics, MM/GBSA, Carbenicillin, Ceforanide, protein-protein interaction inhibitors