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Ductal carcinoma in situ (DCIS) and usual ductal hyperplasia (UDH) represent two extremes on the spectrum of intraductal proliferative lesions of the breast with corresponding differences in invasive carcinoma risk, molecular alteration and therapeutic management. In cases with overlapping morphology, the distinction between DCIS and UDH can be challenging. We performed whole transcriptome analysis on laser-capture microdissected samples from formalin-fixed, paraffin-embedded (FFPE) tissue in two cases of DCIS with UDH-like morphology (DUM) and their corresponding UDH. Of the top 10 genes differentially up/down regulated in DUM compared to UDH, we selected cyclin D1 (upregulated in DUM) and CD117 (c-kit) (down regulated in DUM) and performed immunohistochemical studies using clinically validated antibodies for cyclin D1 and CD117, respectively. Our results showed that both DUM lesions showed strong and diffuse (>50%) nuclear positivity for cyclin D1 antibody. The corresponding foci of UDH showed no reactivity to weak and sparse (<1%) staining for cyclin D1 antibody. Conversely, UDH expressed patchy CD117 (c-kit) positivity, while DUM lesion was completely negative. We also demonstrated that DUM lesions are enriched for genes associated with invasive ducal carcinoma, luminal subtype and brain metastasis. In summary, despite morphological similarities, DUM and UDH are molecularly distinct. Our study showed that whole transcriptome analysis of morphologically distinct lesions from the same FFPE sample isolated by laser capture microdissection provides a powerful tool to identify novel biomarkers in breast cancer.