Heterogeneity of the Alpha-Smooth Muscle Actin Tumor Score in Breast Cancer Cells Significantly Affects Tumor Invasiveness, Recurrence, and Patient Survival

Background: Alpha-smooth muscle actin (αSMA) has been widely investigated in malignancies, primarily concerning its expression in cancer-associated fibroblasts (CAFs) inside the tumor stroma. Microscopic examination indicates that αSMA expression is not confined to the tumor stromal compartment but is also present in a subset of tumor cells, and this expression correlates with an enhanced invasive phenotype of malignant cells from lung, liver, or ovarian malignancies. Information on actin expression in breast cancer (BC) cells is scarce, and its influence on clinicopathological characteristics remains ambiguous due to conflicting findings in the literature.

Objective: To examine the αSMA tumor score in breast cancer cells utilizing digital image analysis (DIA) methodologies and to critically analyze the varying effects of αSMA tumor score values on clinicopathologic parameters, particularly focusing on tumor cell invasiveness, recurrence, and survival.

Materials And Methods: Double immunostaining for CD34 and αSMA was conducted on 53 breast cancer cases that were thoroughly characterized in relation to clinicopathologic data. Double immunostaining for CD34 and αSMA demonstrated different distribution patterns of both markers in normal and breast cancer tissues. DIA data about αSMA tumor cell density, intensity, tumor score, and histological score were correlated with clinicopathological factors.

Results: We delineated three unique breast cancer subgroups based on αSMA tumor scores: a 9.43% low-expressing subgroup (αSMA_TS, score 4), a 35.07% medium-expressing subgroup (αSMA_TS, scores 5 and 6), and a 55.5% high-expressing subgroup (αSMA_TS, scores 7 and 8). Stromal immature vessels and tertiary lymphoid structures (TLS) exhibited a strong correlation with αSMA_TS, whereas recurrence, perineural, and lymphovascular invasion strongly influenced the αSMA_TS and αSMA_TS subgroups. The αSMA_TS subgroup demonstrated the most heterogeneity with the influence of αSMA-expressing breast cancer cells on tumor size, nodal status, perineural and lymphovascular invasion, menopausal status, recurrence, and survival. Most of the cases from the αSMA_TS subgroup had Luminal B and Luminal B-HER2 phenotypes, while triple-negative breast cancer (TNBC) represented one-third of all cases in the αSMA_TS subgroup.

Conclusion: αSMA-expressing breast cancer cells variably affect malignant growth, invasion, and recurrence, highly contingent upon their density and expression intensity. The current investigation identified an αSMA_TS BC subgroup that appears to promote invasiveness, recurrence, and survival in breast cancer. Our data indicate that αSMA BC-expressing cells play a dual role in BC progression, contingent upon their percentage and expression intensity; however, further research is required to elucidate the factors and mechanisms responsible for their accumulation and/or transdifferentiation in malignant breast tissue.