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.

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.

In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution. Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the literature. Indeed, the lack of SFRP1 is associated with both tumor development and patient prognosis. Considering the increased risk of breast tumor development associated with incomplete mammary gland involution, it is crucial to demystify the “grey zone” between physiological age-related involution and tumorigenesis. In this review, we explore the functions of SFRP1 involved in the breast involution processes to understand the perturbations driven by the disappearance of SFRP1 in mammary tissue. Moreover, we question the presence of recurrent microcalcifications identified by mammography. In bone metastases from prostate primary tumor, overexpression of SFRP1 results in an osteolytic response of the tumor cells. Hence, we explore the hypothesis of an osteoblastic differentiation of mammary cells induced by the lack of SFRP1 during lobular involution, resulting in a new accumulation of hydroxyapatite crystals in the breast tissue.

A human transcriptome array on ERα-positive breast cancer continuum of risk identified Secreted Frizzled-Related Protein 1 (SFRP1) as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of SFRP1 in breast carcinogenesis remains, nevertheless, not well understood. In this study, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, in the presence of estradiol (E2) and/or hydroxyapatite microcalcifications (HA). Furthermore, we have modulated SFRP1 expression in breast cancer cell lines, including the MCF10A series, and investigated their tumoral properties. We observed that organoids obtained from multiparous mice were resistant to E2 treatment, while organoids obtained from nulliparous mice developed the luminal phenotype associated with a lower ratio between Sfrp1 and Esr1 expression. The decrease in SFRP1 expression in MCF10A and MCF10AT1 cell lines increased their tumorigenic properties in vitro. On the other hand, the overexpression of SFRP1 in MCF10DCIS, MCF10CA1a, and MCF7 reduced their aggressiveness. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis.