Abstract LB221: Clinical significance of ALDH1L1 expression in hormone receptor positive breast cancer

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Abstract Introduction: Breast cancer is a deadly disease affecting millions of women globally. It is highly heterogeneous, with subtypes such as luminal A, luminal B, HER2-enriched, and TNBC, each exhibiting distinct genetic and clinical characteristics, prognoses, and treatment responses. In breast cancer, metabolic reprogramming is crucial to support rapid tumor growth and survival. Accordingly, breast cancer cells alter the expression of numerous metabolic enzymes to meet their increased demands for energy production and biosynthetic reactions. ALDH1L1, an enzyme of one-carbon metabolism and a candidate tumor suppressor plays an important role in initiation, progression, and resistance to therapy of certain types of malignancies. However, the clinical significance of ALDH1L1 in breast cancer subtypes remains unclear. Methods: Here, we analyzed three cohorts from Seoul National University Hospital: 41 patients with normal and invasive mammary carcinoma samples, 44 paired normal and tumor tissues, and a tissue microarray (TMA) of 1,003 patients with invasive ductal carcinoma. Immunohistochemistry for ALDH1L1 was performed on 1,088 cases, using tissue microarrays or whole section slides. Clinical data, including tumor size, grade, lymphatic invasion, and lymph node metastasis, were obtained from patient records. Publicly available datasets, including METABRIC, were used for the additional analysis of ALDH1L1expression in breast cancer. Cell viability (CCK-8) and clonogenic assays assessed the antiproliferative effect of ALDH1L1 in MCF7 and T47D luminal breast cancer cells. Results: ALDH1L1 expression was significantly higher in non-tumor mammary tissues compared to cancerous tissues (p=0.0014 and p=0.0282), and its expression showed inverse correlations with tumor size, advanced tumor stage, and the presence of lymphatic spread. Further analysis by intrinsic subtypes revealed that higher ALDH1L1 expression was associated with smaller tumor size and lower pT stages in luminal A and HER2+ tumors, as well as lower nuclear grade in triple-negative breast cancer. ALDH1L1 expression was associated with improved overall survival (OS) and disease-free survival (DFS), particularly in hormone receptor (HR)-positive subtypes (OS, p=0.0049; DFS, p=0.0441). Analysis of the METABRIC dataset indicates that breast cancer patients with lower ALDH1L1 expression exhibited poorer OS and DFS rates (p=0.00449 and p=0.0441, respectively). A similar trend was observed in HR-positive breast cancer patients (OS, p=0.0233). Lastly, ALDH1L1 knock-in in MCF7 and T47D cells using lentiviral delivery demonstrated a significant antiproliferative effect in both cell lines. Conclusion: Our study identifies ALDH1L1 as a potential tumor suppressor and favorable prognostic biomarker in breast cancer, particularly in HR-positive subtypes. Higher ALDH1L1 expression was associated with smaller tumor size, lower tumor stage, and improved overall and disease-free survival. Additionally, functional assays showed that ALDH1L1 expression inhibits cell proliferation in luminal breast cancer cell lines. These findings highlight the clinical significance of ALDH1L1 in breast cancer prognosis and its potential as a therapeutic target. Citation Format: Amira A. Abdellatef, Han Suk Ryu, Da Sol Kim, Ilias P. Nikas, Sergey Krupenko. Clinical significance of ALDH1L1 expression in hormone receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB221.

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