Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development

Abstract

Seven classes of mitogen-activated protein kinase (MAPK) intracellular signalling cascades exist, four of which are implicated in breast disease and function in mammary epithelial cells. These are the extracellular regulated kinase (ERK)1/2 pathway, the ERK5 pathway, the p38 pathway and the c-Jun N-terminal kinase (JNK) pathway. In some forms of human breast cancer and in many experimental models of breast cancer progression, signalling through the ERK1/2 pathway, in particular, has been implicated as being important. We review the influence of ERK1/2 activity on the organised three-dimensional association of mammary epithelial cells, and in models of breast cancer cell invasion. We assess the importance of epidermal growth factor receptor family signalling through ERK1/2 in models of breast cancer progression and the influence of ERK1/2 on its substrate, the oestrogen receptor, in this context. In parallel, we consider the importance of these MAPK-centred signalling cascades during the cycle of mammary gland development. Although less extensively studied, we highlight the instances of signalling through the p38, JNK and ERK5 pathways involved in breast cancer progression and mammary gland development.

Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1α Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium

“…The observations in the present study indicate that activation of p38 is EGFR-dependent in Cr(VI)-transformed cells. Activation of p38 has been shown to correlate with increased tumor malignancy and poor prognosis of cancer patients (39,40). Although hypoxia up-regulates HIF-1␣ through p38 in various cells (41), it has been reported that activation of p38 by hypoxia is mediated by HIF-1␣ in human hepatoma BEL-7405 cells (41).…”

Identification of Novel Ras-Cooperating Oncogenes in Drosophila melanogaster: A RhoGEF/Rho-Family/JNK Pathway Is a Central Driver of Tumorigenesis

“…The association of a high JNK signature in ER 1 /HER2 2 ("luminal" subtype) breast cancers is also consistent with reports from previous clinical studies and xenograft models of tamoxifen resistance, which have reported a positive association with activated/phosphorylated JNK ( Johnston et al 1999;Schiff et al 2000), although these tumors do not show high expression of the Ras signature ( Figure 7E). While Ras is not an established oncogene in breast cancer, Ras pathway upregulation is recognized to be important for breast cancer growth and tumorigenesis (reviewed by Whyte et al 2009), and our data support a link between Ras and JNK signaling in HER2 1 breast cancers. Together these data support further investigation into the relationship between JNK and Ras signaling in human cancers.…”

High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells

“…Further, high glucoseinduced phosphorylation of p38 in human endothelial cells leads to cell death (Nakagami et al 2001). ERK1/2 activity is associated with invasive and metastatic properties (Whyte et al 2009); its activation results in desensitization of pore opening and increased resistance to death stimuli, providing advantage to tumor cells (Rasola et al 2010). Our results show that cellular stress under a high-glucose condition in MCF-7 cells results in activation of p38 and de-phosphorylation of ERK, thereby leading to cell death.…”