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Simple Summary  Ductal carcinoma in situ (DCIS) is an early-stage breast cancer (BC), in which tumor cells are growing in a localized duct of the mammary gland. DCIS is considered a precursor disease for invasive BC and, therefore, treated as soon as it is identified. However, low-grade DCIS can be confused with atypical ductal hyperplasia, which is not a malignant lesion, leading to unnecessary surgery in around 70% of women with suspected DCIS. On the other hand, if left untreated, a DCIS has the potential to progress to IDC. In this retrospective study, we identified a gene signature,  carboxypeptidase B1  ( CPB1) , the expression of which could help differentiate DCIS from an ADH lesion and DCIS that may progress to an invasive BC.    Abstract  Ductal carcinoma in situ (DCIS) is considered a non-obligatory precursor for invasive ductal carcinoma (IDC). Around 70% of women with atypical ductal hyperplasia (ADH) undergo unnecessary surgery due to the difficulty in differentiating ADH from low-grade DCIS. If untreated, 14–60% of DCIS progress to IDC, highlighting the importance of identifying a DCIS gene signature. Human transcriptome data of breast tissue samples representing each step of BC progression were analyzed and high expression of  carboxypeptidase B1  ( CPB1 ) expression strongly correlated with DCIS. This was confirmed by quantitative PCR in breast tissue samples and cell lines model. High  CPB1  expression correlated with better survival outcome, and mRNA level was highest in DCIS than DCIS adjacent to IDC and IDC. Moreover, loss of CPB1 in a DCIS cell line led to invasive properties associated with activation of  HIF1α , FN1, STAT3 and  SPP1  and downregulation of SFRP1 and  OS9 . The expression of CPB1 could predict 90.1% of DCIS in a cohort consisting of DCIS and IDC. We identified CPB1, a biomarker that helps differentiate DCIS from ADH or IDC and in predicting if a DCIS is likely to progress to IDC, thereby helping clinicians in their decisions.

Is Carboxypeptidase B1 a Prognostic Marker for Ductal Carcinoma In Situ?