Prolactin synergizes with canonical Wnt signals to drive development of ER+ mammary tumors via activation of the Notch pathway.

Prolactin (PRL) cooperates with other factors to orchestrate mammary development and lactation, and is epidemiologically linked to higher risk for breast cancer. However, how PRL collaborates with oncogenes to foster tumorigenesis and influence breast cancer phenotype is not well understood. To understand its interactions with canonical Wnt signals, which elevate mammary stem cell activity, we crossed heterozygous NRL-PRL mice with Apc mice and treated pubertal females with a single dose of mutagen. PRL in the context of Apc fueled a dramatic increase in tumor incidence in nulliparous mice, compared to Apc alone. Although carcinomas in both NRL-PRL/Apc and Apc females acquired a mutation in the remaining wildtype Apc allele and expressed abundant β-catenin, PRL-promoted tumors displayed higher levels of Notch-driven target genes and Notch-dependent cancer stem cell activity, compared to β-catenin-driven activity in Apc tumors. This PRL-induced shift to dominant Notch signals was evident in preneoplastic epithelial hyperplasias at 120 days of age. In NRL-PRL/Apc females, rapidly proliferating hyperplasias, characterized by β-catenin at cell junctions and high NOTCH1 expression, contrasted with slower growing lesions with nuclear β-catenin in Apc females. These studies demonstrate that PRL can powerfully modulate the incidence and phenotype of mammary tumors, shedding light on mechanisms whereby PRL elevates risk of breast cancer.