Abstract P4-02-14: Breast cancer cell/adipocyte crosstalk in obesity hampers the efficacy of tamoxifen

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Abstract Despite the improvements in the outcomes of breast cancer patients following the implementation of endocrine therapy into daily oncology practice, the development of ‘de novo’ or acquired resistance to these treatments has become a major limitation. To date, several hallmarks of hormonal resistance have been proposed, including ERα loss or mutations, activation of growth factor-mediated signaling pathways, and alterations of key cell cycle checkpoints. More recently, it was proven that a reduced response to these therapeutic regimens may rely not only on tumor-cell intrinsic factors, but it is also dependent on the surrounding microenvironment and on the host characteristics. Indeed, clinical studies have suggested that obesity, in addition to promoting breast cancer development and progression, represents a heavyweight player driving breast cancer endocrine resistance. However, the influence of adipocytes and their secretome on the efficacy of hormone therapy has not properly investigated. In a model of co-culture, we demonstrated that the anti-proliferative effects of Tamoxifen on anchorage-dependent and anchorage-independent growth of MCF-7 breast cancer cells were counteracted by conditioned media (CM) released by fully differentiated 3T3-L1 cells (3T3-L1 A), a widely used 'in vitro' model of white adipocytes. Moreover, pre-incubation of MCF-7 cells with adipocyte-derived CM reduced their sensitivity to the inhibitory effects of Tamoxifen on motility, as evidenced by wound-healing and transmigration assays. Interestingly, the growth and the motility of Tamoxifen-resistant breast cancer cells were dramatically increased in the presence of adipocyte-derived CM, further suggesting a supportive role of adipocyte secretome in the development and progression of endocrine-resistant phenotypes. Quantitative transcriptome profiling of Tamoxifen-resistant cells revealed 917 differentially expressed genes (FDR ≤ 0.05), of which 243 were upregulated and 180 were downregulated in response to adipocyte-CM. Among these major modifications, the most significant down-regulated gene was Thioredoxin-interacting protein (TXNIP, 5-fold), a tumor suppressor participating in the metabolic reprogramming and oxidative stress in various solid cancers. These results well correlated with data obtained in retrospective analyses showing that low TXNIP expression in breast cancer patients was associated with a statistically significant poorer recurrence-free (RFS), overall (OS), post-progression (PPS) and distant metastasis-free (DMFS) survival compared to high TXNIP-expressing patients. This relevant discrimination is also achieved in tamoxifen-treated patients, highlighting a role of TXNIP for identifying patients at high risk of progression. These findings bring insights on adipocytes and mammary cancer cell interactions during Tamoxifen therapy, particularly in overweight/obese people and add evidence to advocating obesity as a parameter to be considered when identifying treatments for patients with ER-positive breast cancer. Citation Format: Amanda Caruso, Luca Gelsomino, Giusi La Camera, Cinzia Giordano, Salvatore Panza, Daniela Bonofiglio, Stefania Catalano, Sebastiano Andò, Ines Barone. Breast cancer cell/adipocyte crosstalk in obesity hampers the efficacy of tamoxifen [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-14.