Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, University of Pecs, Szigeti ut 12, Pecs, 7624, Hungary.
J Mol Neurosci. 2014 Jan;52(1):28-36. doi: 10.1007/s12031-013-0193-3. Epub 2013 Dec 10.
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with trophic and cytoprotective effects, has been shown to affect cell survival, proliferation, and also differentiation of various cell types. The high PACAP level in the milk and its changes during lactation suggest a possible effect of PACAP on the differentiation of mammary epithelial cells. Mammary cell differentiation is regulated by hormones, growth factors, cytokines/chemokines, and angiogenic proteins. In this study, differentiation was hormonally induced by lactogenic hormones in confluent cultures of HC11 mouse mammary epithelial cells. We investigated the effect of PACAP on mammary cell differentiation as well as release of cytokines, chemokines, and growth factors. Differentiation was assessed by expression analysis of the milk protein β-casein. Differentiation significantly decreased the secretion of interferon gammainduced protein (IP)-10, "regulated upon activation normal T cell expressed and presumably secreted" (RANTES), insulin-like growth factor-binding protein (IGFBP)-3 and the epidermal growth factor receptor (EGFR) ligands, such as epidermal growth factor (EGF) and amphiregulin (AREG). The changes in the levels of IP-10 and RANTES may be relevant for the alterations in homing of T cells and B cells at different stages of mammary gland development, while the changes of the EGFR ligands may facilitate the switch from proliferative to lactating stage. PACAP did not modulate the expression of β-casein or the activity of hormone-induced pathways as determined by the analysis of phosphorylation of Akt, STAT5, and p38 MAPK. However, PACAP decreased the release of EGF and AREG from non-differentiated cells. This may influence the extracellular signal-related transactivation of EGFR in the non-differentiated mammary epithelium and is considered to have an impact on the modulation of oncogenic EGFR signaling in breast cancer.
垂体腺苷酸环化酶激活肽（PACAP）是一种具有营养和细胞保护作用的神经肽，已被证明能影响各种细胞类型的细胞存活、增殖和分化。牛奶中高水平的 PACAP 及其在哺乳期的变化表明 PACAP 可能对乳腺上皮细胞的分化有影响。乳腺细胞的分化受激素、生长因子、细胞因子/趋化因子和血管生成蛋白的调节。在这项研究中，我们在 HC11 小鼠乳腺上皮细胞的汇合培养物中用泌乳激素诱导分化，并研究了 PACAP 对乳腺细胞分化以及细胞因子、趋化因子和生长因子释放的影响。分化通过乳蛋白β-酪蛋白的表达分析来评估。分化显著降低干扰素诱导蛋白（IP）-10、“正常 T 细胞激活后表达和假定分泌”（RANTES）、胰岛素样生长因子结合蛋白（IGFBP）-3 和表皮生长因子受体（EGFR）配体，如表皮生长因子（EGF）和双调蛋白（AREG）的分泌。IP-10 和 RANTES 水平的变化可能与 T 细胞和 B 细胞在乳腺发育不同阶段归巢的改变有关，而 EGFR 配体的变化可能有利于从增殖期向泌乳期的转变。PACAP 并没有调节β-酪蛋白的表达或激素诱导途径的活性，这可以通过分析 Akt、STAT5 和 p38 MAPK 的磷酸化来确定。然而，PACAP 减少了未分化细胞中 EGF 和 AREG 的释放。这可能影响未分化乳腺上皮细胞中 EGFR 的细胞外信号相关转激活，并且被认为对乳腺癌中致癌 EGFR 信号的调节有影响。
