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Clinically determined Ki-67 is a well-established marker for assessing proliferation potential in breast and other cancers. However, Ki-67 and the recommended thresholds for clinical decision-making vary systematically across breast cancer subtypes. In this study, an analysis of published gene expression data against Ki-67 in ER+/HER2- and Luminal A ductal carcinomas identified 127 of 14,997 protein-coding genes (elastic-net coefficient ≠ 0). The most upregulated genes associated with high Ki-67 are involved in cancer proliferation and were known in breast cancer studies, while the downregulated genes are involved in diverse signaling transduction processes. Application of the identified gene signature to ER+/HER2- and Luminal A ductal carcinomas consistently stratified two independent, population-based breast cancer cohorts. Although the ER+/HER2- clinical and the Luminal A intrinsic subtypes typically show good prognosis, one subpopulation identified by the signature showed an elevated risk of disease recurrence (hazards ratios 1.59 [95% CI 1.02, 2.47] and 3.80 [95% CI 0.83, 17.27] in two independent application cohorts). The present study identifies a proliferation gene signature specific to ER+/HER2- and Luminal A ductal carcinomas, provides biological insight into the more proliferative cancers, and could be a basis for future therapeutic development.
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