ERα–CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis

Abstract

Expression microarray analysis identified over 930 genes regulated during puberty in the mouse mammary gland. Most prominent were genes whose expression increased in parallel with pubertal development and remained high thereafter. Members of the Wnt, transforming growth factor-b and oestrogen-signalling pathways were significantly overrepresented. Comparison to expression data from CITED1 knockout mice identified a subset of oestrogen-responsive genes displaying altered expression in the absence of CITED1. Included in this subset are stanniocalcin2 (Stc2) and amphiregulin (Areg). Chromatin immunoprecipitation revealed that ERa binds to oestrogen response elements in both the Stc2 and Areg genes in the mammary gland during puberty. Additionally, CITED1 and ERa localize to the same epithelial cells of the pubertal mammary gland, supporting a role for interaction of these two proteins during normal development. In a human breast cancer data set, expression of Stc2, Areg and CITED1 parallel that of ERa. Similar to ERa, CITED1 expression correlates with good outcome in breast cancer, implying that potential maintenance of the ERa-CITED1 co-regulated signalling pathway in breast tumours can indicate good prognosis.

TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex

“…In human breast cancer samples, CITED1 expression parallels that of ER (McBryan et al, 2007). Therefore, both the proteins TOX3 and CITED1 seem to be implicated with breast cancer and estrogendependent signal transduction.…”

Patterns of cell signaling pathway activation that characterize mammary development

“…In addition to these datasets that encompass pregnancy, lactation and involution, several recent reports focused on pubertal ductal outgrowth McBryan et al, 2007). Using a strategy to compare terminal end buds (TEBs) with ducts, it was noted that GATA3 was highly expressed and was essential for mammary development .…”

“…A number of groups have analyzed the transcriptional changes associated with the various developmental phases of the mammary gland (Blanchard et al, 2007;Clarkson et al, 2004;Master et al, 2002;McBryan et al, 2007;Rudolph et al, 2007;Stein et al, 2004). Three reports are notable for their comprehensive coverage of the spectrum of development from virgin through pregnancy, lactation and involution (Clarkson et al, 2004;Master et al, 2002;Stein et al, 2004).…”

Review of: Metalloproteinase axes increase β-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3

“…Intriguingly, the only endogenous inhibitor of ADAM17 is TIMP3, which is downregulated in the TEBs but is present in the subtending ducts. High levels of AR expression have been found in a large cohort of human breast tumors and in hyperplastic enlarged lobular units (HELUs), which are potential precursors of breast cancer [13,23]. In this paper, Khokha et al demonstrate that TIMP3 can enhance signaling through a b-catenin/ Lef pathway in mouse MECs.…”

“…Growth of the mammary tree occurs at the tips of the ducts from the terminal end buds (TEBs). This is an invasive process and specific genes that have been implicated in tumor cell metastasis are activated in the mammary epithelium and/or stroma during this developmental period [13]. In addition, since 90% of breast cancers are of ductal origin, delineating the systemic and local factors that regulate ductal growth may provide important clues to factors that contribute to the early genesis of breast cancer.…”