AbstractInvasive lobular carcinoma (ILC) is a low‐ to intermediate‐grade histological breast cancer type caused by mutational inactivation of E‐cadherin function, resulting in the acquisition of anchorage independence (anoikis resistance). Most ILC cases express estrogen receptors, but options are limited in relapsed endocrine‐refractory disease as ILC tends to be less responsive to standard chemotherapy. Moreover, ILC can relapse after >15 years, an event that currently cannot be predicted. E‐cadherin inactivation leads to p120‐catenin‐dependent relief of the transcriptional repressor Kaiso (ZBTB33) and activation of canonical Kaiso target genes. Here, we examined whether an anchorage‐independent and ILC‐specific transcriptional program correlated with clinical parameters in breast cancer. Based on the presence of a canonical Kaiso‐binding consensus sequence (cKBS) in the promoters of genes that are upregulated under anchorage‐independent conditions, we defined an ILC‐specific anoikis resistance transcriptome (ART). Converting the ART genes into human orthologs and adding published Kaiso target genes resulted in the Kaiso‐specific ART (KART) 33‐gene signature, used subsequently to study correlations with histological and clinical variables in primary breast cancer. Using publicly available data for ER^POSHer2^NEG breast cancer, we found that expression of KART was positively associated with the histological ILC breast cancer type (p < 2.7E‐07). KART expression associated with younger patients in all invasive breast cancers and smaller tumors in invasive ductal carcinoma of no special type (IDC‐NST) (<2 cm, p < 6.3E‐10). We observed associations with favorable long‐term prognosis in both ILC (hazard ratio [HR] = 0.51, 95% CI = 0.29–0.91, p < 3.4E‐02) and IDC‐NST (HR = 0.79, 95% CI = 0.66–0.93, p < 1.2E‐04). Our analysis thus defines a new mRNA expression signature for human breast cancer based on canonical Kaiso target genes that are upregulated in E‐cadherin deficient ILC. The KART signature may enable a deeper understanding of ILC biology and etiology. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.