Role of Secreted Frizzled-Related Protein 1 in Early Breast Carcinogenesis and Breast Cancer Aggressiveness

SIMPLE SUMMARY: Secreted Frizzled-Related Protein 1 (SFRP1) expression is decreased during breast cancer progression and inversely associated with breast tissue age-related lobular involution in women. In this study, we have investigated the potential causal role of the decrease in SFRP1 expression in early breast carcinogenesis. In order to do so, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, and modulated SFRP1 expression in breast non-tumoral and tumoral cell lines from multiple molecular subtypes. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis. ABSTRACT: 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.