Long noncoding RNAs (lncRNAs) have outnumbered protein-coding genes, yet the majority have unknown function. We previously discovered over 800 lncRNAs at breast cancer risk regions. However, developing a low-cost and accurate 3D model to identify functional genes in high-throughput CRISPR screens is challenging. Here, we devised a scalable breast cancer spheroid model and performed a pooled CRISPR-Cas13d RNA knockdown screen (~20,000 guides) in 3D and in vivo. We identified 50–100 lncRNAs involved in cell proliferation, with about 30% overlap between 3D and in vivo hits. Our findings highlight lncRNAs as mediators of breast cancer risk and introduce a robust spheroid CRISPR platform for mapping phenotypes associated with lncRNAs.