P22 | EXPLORING THE UNEXPECTED DUAL ROLE OF GARLIC DERIVATIVES IN REGULATING INVASIVENESS IN BREAST CANCER SUBTYPES

M. Dell’Aira¹, S. Grassilli², M. Pierantoni¹, V. Bertagnolo¹, F. Brugnoli¹ | ¹Department of Translational Medicine, University of Ferrara, Ferrara, Italy; ²Department of Environmental Sciences and Prevention and LTTA Centre, University of Ferrara, Ferrara, Italy

Breast cancer includes tumor subtypes with distinct morphological, molecular, and clinical profiles. The intrinsic heterogeneity, combined with the toxicity of chemotherapeutics, often impacts therapeutic efficacy and contributes to the development of resistance¹. Therefore, there is growing interest in identifying adjuvant strategies to enhance the effectiveness of conventional treatments. Among these, natural compounds are gaining attention due to their broad biological activities and relatively low toxicity. Garlic (Allium sativum) has been extensively studied for its anticancer properties, with several reports indicating its ability to counteract breast tumor aggressiveness². However, studies fail to account for the high heterogeneity within triple-negative breast cancer (TNBC), and no data are currently available about its effects on HER2+ tumors, which, despite recent therapeutic advances, frequently develop resistance. To address this gap, we investigated the effects of garlic-derivatives on PDX-derived TNBC and HER2+ breast cancer cells. Interestingly, in TNBC cells we found a selective molecular subtype-dependent decrease of the invasive potential³, while a dual effect was shown in HER2+ cells, with reduced invasiveness after a short-term exposure, and a paradoxically enhanced invasive potential after prolonged treatment. In both TNBC and HER2+ cell models, modulation of invasiveness was associated with activation of the Akt/GSK3β/βcatenin signaling axis, culminating in nuclear accumulation of βcatenin, a key regulator of genes involved in tumor progression and malignancy⁴. Although in vivo validation is required, our findings highlight the importance of understanding the precise molecular mechanisms triggered by natural compounds in specific tumor contexts. These results also raise concerns about the uncritical use of natural substances in oncology, as their effects may vary depending on tumor subtype and treatment conditions.