The
peptide hormone prolactin (PRL) and certain members of the
epidermal growth factor (
EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary
tumorigenesis. Our recent studies have revealed that the CUB and zona pellucida-like domain-containing
protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the
transcription factor STAT5 in mouse mammary epithelium. Of note, CUZD1 controls production of a specific subset of the
EGF family
growth factors and consequent activation of their receptors. Here, we found that consistent with this finding, CUZD1 overexpression in non-transformed mammary epithelial HC11 cells increases their proliferation and induces tumorigenic characteristics in these cells. When introduced orthotopically in mouse mammary glands, these cells formed
adenocarcinomas, exhibiting elevated levels of STAT5 phosphorylation and activation of the
EGF signaling pathway. Selective blockade of STAT5 phosphorylation by
pimozide, a small-molecule inhibitor, markedly reduced the production of the
EGF family
growth factors and inhibited PRL-induced
tumor cell proliferation in vitro
Pimozide administration to mice also suppressed CUZD1-driven mammary
tumorigenesis in vivo Analysis of human MCF7
breast cancer cells indicated that CUZD1 controls the production of the same subset of
EGF family members in these cells as in the mouse. Moreover,
pimozide treatment reduced the proliferation of these
cancer cells. Collectively, these findings indicate that overexpression of CUZD1, a regulator of
growth factor pathways controlled by PRL and STAT5, promotes mammary
tumorigenesis. Blockade of the STAT5 signaling pathway downstream of CUZD1 may offer a therapeutic strategy for managing these
breast tumors.