Androgen Receptor Emerges as a Marker of Differentiation in Endometrial Cancer

In endometrial carcinoma (EC), the molecular landscape is increasingly guiding clinical stratification. While estrogen and progesterone receptors (ER and PR) have long been central to hormone-responsive classification, a growing body of evidence—now reinforced by a retrospective study from Paudice et al.—suggests the androgen receptor (AR) may provide complementary prognostic and therapeutic insight, particularly in low-grade disease.

Profiling AR Expression Across EC Subtypes
This observational study assessed AR expression in 143 EC specimens, analyzing its associations with classical prognostic markers, molecular features, and clinicopathologic subtypes. The tumors were categorized into three subtypes:

• Low-grade endometrioid carcinoma (LGEC)
• High-grade endometrioid carcinoma (HGEC)
• Other high-grade EC (OHEC), including serous and clear cell carcinomas

AR status was compared against immunohistochemical (IHC) profiles including ER, PR, Ki-67, p53, β-catenin, E-cadherin, Bcl-2, Cyclin D1, and mismatch repair (MMR) proteins.

AR Reflects Hormonal Differentiation, Not Aggressiveness
Key observations reinforce AR as a marker of hormonal differentiation:

• AR expression was highest in LGEC, averaging 27.7 percent versus 11.0 percent in HGEC and 15.6 percent in OHEC (p = 0.0159), supporting its association with less aggressive phenotypes.
• Strong positive correlations were observed between AR and both ER (p = 0.0048) and PR (p = 0.0001), consistent with shared hormonal regulatory pathways.
• In contrast, AR expression showed no significant correlation with proliferation (Ki-67), tumor suppressor status (p53), or other markers of aggressiveness such as Cyclin D1 and β-catenin.
• Importantly, AR status did not associate with FIGO stage, tumor invasion pattern, or microsatellite instability (MMR status), reinforcing its specificity for tumor differentiation rather than progression.

While not statistically significant, a borderline trend (p = 0.062) suggested that AR-high tumors may be modestly enriched for tumor-infiltrating lymphocytes (TILs). This hints at a possible interaction between AR signaling and the immune microenvironment—a hypothesis requiring deeper immunologic profiling in future studies.

AR as a Stratification Tool and Therapeutic Target
In hormone receptor-positive (ER/PR) ECs, AR may serve as an adjunctive marker for prognosis and help refine risk stratification. Of note, the presence of AR in select ER/PR-low tumors suggests an opportunity for AR-targeted therapies, an approach already in use for prostate cancer and under investigation in breast cancer.

Potential applications moving forward include:

• Diagnostic Utility: AR could be integrated into IHC panels to better delineate hormone-responsive EC subtypes, especially where ER/PR profiles are ambiguous.
• Therapeutic Development: Investigating AR antagonists in AR-positive EC, including trials in ER/PR-low or hormone-refractory settings, could expand treatment options.
• Molecular Classification: AR status might refine current molecular risk models, particularly in low-grade EC, where precision stratification remains challenging.

Reference:

1. Paudice M, Greppi M, Valle L, et al. The role of the Androgen Receptor (AR) in endometrial cancer aggressiveness: Correlation with other prognostic markers and therapeutic implications. A retrospective observational study. Pathol Res Pract. 2025;269:155922. doi:10.1016/j.prp.2025.155922