Disruption of Steroid and Prolactin Receptor Patterning in the Mammary Gland Correlates with a Block in Lobuloalveolar Development

Abstract

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-beta (C/EBPbeta), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrlR) expression were observed while screening for differentially expressed genes in C/EBPbeta(null) mice. PR patterning was also altered in PrlR(null) mice, as well as in mammary tissue transplants from both PrlR(null) and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation. Down-regulation of PR and activation of Stat5 phosphorylation were seen after estrogen and progesterone treatment in both C/EBPbeta(null) and wild-type mice, indicating that these signaling pathways were functional, despite the failure of steroid hormones to induce proliferation. IGF binding protein-5, IGF-II, and insulin receptor substrate-1 all displayed altered patterns and levels of expression in C/EBPbeta(null) mice, suggestive of a change in the IGF signaling axis. In addition, small proline-rich protein (SPRR2A), a marker of epidermal differentiation, and keratin 6 were misexpressed in the mammary epithelium of C/EBPbeta(null) mice. Together, these data suggest that C/EBPbeta is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrlR expression is a critical determinant of hormone-regulated cell proliferation.

The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer

“…The full list of genes that were up-or down-regulated in this analysis can be found in Supplemental Table S2. estrogen receptor (ERa) and the progesterone receptor (PR) was observed in many breast tumors. 50,52,53 Previous reports demonstrated that PRL up-regulated PR 50 and ERa in breast cancer cells 54,55 ; this induction was observed only after prolonged PRL stimulation (approximately 24 to 72 hours). We, therefore, examined the effects of prolonged PRL exposure on ERa/PR mRNA levels in PRLr or PRLrYDmut-expressing MCF7 cells.…”

“…Co-expression of the PRLr with ERa and PR is observed in many breast tumors, 50,52,53,89 and prolonged PRL exposure increases ERa and PR levels in the ER/PRpositive breast cancer cell lines, T47D and MCF7. 50,55 These observations suggest that the transcriptional cross regulation of PRLr, ERa, and PR may contribute to their co-expression in breast cancer.…”

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

“…C/EBPβ −/− mice display overexpression and disruption of cellular PR expression that coincides with a 10-fold decrease in mammary cell proliferation following steroid stimulation (Seagroves et al, 2000). The mammary glands of these mice also display similar changes in the level and pattern of PrlR in addition to aberrant ductal morphogenesis and decreased lobular alveolar development (Grimm et al, 2002). Herein, we have shown that both PR-A and PR-B are capable of inducing expression of PrlR, the former in an unliganded manner and the latter upon binding P. In the mouse, PR-A is associated with ductal elongation; PR-B is associated with lobuloalveolar development (Shyamala et al, 2000).…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…It is also produced locally by multiple extrapituitary sites, including the mammary epithelium, placenta, uterus, bone, brain and immune system, and can act in an autocrine/ paracrine manner (Ben-Jonathan et al, 1996;Freeman et al, 2000). PRL stimulates normal mammary growth, development and lactation, but also affects other reproductive aspects,such as osmoregulation, stress and behavior (Horseman, 1999;Rui, 2000;Hovey et al, 2001;Goffin et al, 2002;Grimm et al, 2002). Although controversial, the contribution of PRL to the pathogenesis and progression of human breast cancer is increasingly appreciated (Hankinson et al, 1999;Vonderhaar, 1999;Llovera et al, 2000b;Ben-Jonathan et al, 2002;Clevenger et al, 2003).…”