Tumour architecture inverts ARNT-dependent growth regulation and reveals CPE-mediated spheroid expansion in luminal breast cancer

ARNT is a prominent architecture-dependent fitness regulator in luminal breast cancer, where ARNT depletion reduces 2D proliferation but enhances 3D spheroid growth.

• Why it matters: Functional genomic screens often use 2D cultures, potentially missing how tumor architecture reshapes gene control of cancer growth.
• What they did: Parallel chromosome 1q focused CRISPR screens compared matched 2D monolayers and 3D spheroids in luminal breast cancer cells, followed by transcriptomics, epistasis, and correlation analyses in TCGA and single-cell data.
• The result: CPE acts downstream of ARNT: CPE is required for ARNT-loss-driven spheroid expansion, sufficient to restore growth in ARNT-overexpressing spheroids, and ARNT–CPE are inversely correlated in low-hypoxia TCGA Luminal A and within ER positive cancer cells.

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