Abstract
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.
Highlights
Introduction ofHC11-Cuzd1 cells into the mammary gland generates adenocarcinomasTo further evaluate the tumorigenic properties of HC11Cuzd1 cells in vivo, these cells were mixed with Matrigel and orthotopically injected into the mammary gland duct of nude mice through the nipple
We tested the concept that overexpression of CUZD1 in mammary epithelial cells may drive constitutive activation of the signal transducer and activator of transcription 5 (STAT5) pathway and inappropriate stimulation of the epidermal growth factor (EGF) family growth factor pathways, leading to uncontrolled cell proliferation. We demonstrate that such dysregulation of CUZD1 and its downstream STAT5 and EGF receptor pathways leads to breast carcinoma
We previously reported that loss of STAT5 phosphorylation in Cuzd1null mammary epithelium is coincident with the lack of production of a subset of EGF family ligands in this tissue [51]
Summary
To test whether the overexpression of Cuzd promotes transformation of mammary epithelial cells, we employed HC11 cells, a non-transformed mammary epithelial cell line derived from pregnant BALB/c mice. We previously reported that loss of STAT5 phosphorylation in Cuzd1null mammary epithelium is coincident with the lack of production of a subset of EGF family ligands in this tissue [51] Consistent with this finding, we report here that inhibition of STAT5 by pimozide reduced the expression of Ereg and Epgn transcripts in HC11-Cuzd cells (Fig. 5C), confirming that inhibition of STATS signaling inhibits growth factor pathways critical for tumor cell proliferation. Markedly inhibited the proliferation of MCF7-Cuzd in growth medium containing serum (Fig. 8E) These results indicated that CUZD1-mediated activation of STAT5 signaling and downstream activation of ErbB1 and ErbB4 pathways are likely to play a critical role in controlling the proliferation of certain types of human breast cancer cells, and the use of pimozide is highly effective in countering the growth of these cells
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