HGNC Approved Gene Symbol: EREG
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:74,365,145-74,388,749 (from NCBI)
Toyoda et al. (1995) purified a member of the epidermal growth factor (EGF; 131530) family, termed epiregulin. Epiregulin functions as a tumor growth-inhibitory factor inducing morphologic changes in HeLa cells. Purified mouse epiregulin contains 46 amino acid residues with 24 to 50% sequence identity with other members of the EGF family and exhibits low affinity for the EGF receptor (131550) on human epidermoid carcinoma A431 cells. Toyoda et al. (1997) cloned and expressed the human epiregulin gene. Their results showed that, although other members of the EGF family are ubiquitously expressed in normal tissues, the level of expression of epiregulin was extremely low but clearly detectable in macrophages and placenta and was high in carcinoma cells.
Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by luteinizing hormone (LH; see 152780) in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor (LHR; 152790) to mural granulosa cells (Peng et al., 1991). Park et al. (2004) demonstrated that LH stimulation in wildtype mouse ovaries induces the transient and sequential expression of the epidermal growth factor family members amphiregulin (104640), epiregulin, and betacellulin (600345). Incubation of follicles with these growth factors recapitulates the morphologic and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, Park et al. (2004) concluded that these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.
By activating Erk (see MAPK3; 601795) and p38 Mapk (MAPK14; 600289) in differentiated rat aorta vascular smooth muscle cells (VSMCs), Takahashi et al. (2003) dedifferentiated the cells and identified epiregulin as a secreted autocrine/paracrine dedifferentiation factor. Unsaturated lysophosphatidic acid and PDGFB (190040) homodimers, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an Erk- and p38 Mapk-dependent manner. RT-PCR and immunohistochemical analysis revealed restricted expression of epiregulin in human atherosclerotic arteries and balloon-injured rat arteries. Takahashi et al. (2003) hypothesized that epiregulin may be involved in progression of vascular remodeling, such as atherosclerosis.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including EREG, were functionally validated. Two that were not functionally validated but that achieved the highest statistical significance (P less than 0.000001) were FSCN1 (602689) and angiopoietin-like 4 (ANGPTL4; 605910). Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Metastasis entails numerous biologic functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacologic approaches, Gupta et al. (2007) showed that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2 (600262), and the matrix metalloproteinases MMP1 (120353) and MMP2 (120360), when expressed in human breast cancer cells, collectively facilitate the assembly of new tumor blood vessels, the release of tumor cells into the circulation, and the breaching of lung capillaries by circulating tumor cells to seed pulmonary metastasis. Gupta et al. (2007) concluded that their findings revealed how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biologic activities can be therapeutically targeted with specific drug combinations.
The skin has a versatile system of immune surveillance. Upon damage, biologically active interleukin-1-alpha (IL1A; 147760) is released to extracellular space from keratinocytes and is a major player in skin inflammation. Shirasawa et al. (2004) showed that epiregulin is expressed not only in keratinocytes but also in tissue-resident macrophages, and that epiregulin-deficient (Ereg -/-) mice develop chronic dermatitis. Wound healing in the skin in Ereg-null mice was not impaired in vivo, nor was the growth rate of keratinocytes from null mice different from that of wildtype mice in vitro. Of interest was that in wildtype keratinocytes, both IL1-alpha and the secreted form of EREG induced downregulation of IL18 (600953) mRNA expression; overexpression of IL18 in the epidermis was reported to induce skin inflammation in mice, whereas the downregulation of IL18 induced by IL1-alpha was impaired in Ereg-null keratinocytes. Although bone marrow transfer experiments indicated that Ereg deficiency in non-bone-marrow-derived cells is essential for the development of dermatitis, production of proinflammatory cytokines by Ereg -/- mouse macrophages in response to Toll-like receptor agonists was much lower compared with wildtype macrophages. Addition of recombinant mouse Ereg to Toll-like receptor agonist-stimulated macrophages did not increase cytokine production, suggesting that secreted Ereg does not affect these responses. These findings taken together suggested that Ereg plays a critical role in immune/inflammatory-related responses of keratinocytes and macrophages at the barrier from the outside milieu and that the secreted and membrane-bound forms of EREG have distinct functions.
Gupta, G. P., Nguyen, D. X., Chiang, A. C., Bos, P. D., Kim, J. Y., Nadal, C., Gomis, R. R., Manova-Todorova, K., Massague, J. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446: 765-770, 2007. [PubMed: 17429393] [Full Text: https://doi.org/10.1038/nature05760]
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., Massague, J. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. [PubMed: 16049480] [Full Text: https://doi.org/10.1038/nature03799]
Park, J.-Y., Su, Y.-Q., Ariga, M., Law, E., Jin, S.-L. C., Conti, M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 303: 682-684, 2004. [PubMed: 14726596] [Full Text: https://doi.org/10.1126/science.1092463]
Peng, X.-R., Hsueh, A. J. W., LaPolt, P. S., Bjersing, L., Ny, T. Localization of luteinizing hormone receptor messenger ribonucleic acid expression in ovarian cell types during follicle development and ovulation. Endocrinology 129: 3200-3207, 1991. [PubMed: 1954899] [Full Text: https://doi.org/10.1210/endo-129-6-3200]
Shirasawa, S., Sugiyama, S., Baba, I., Inokuchi, J., Sekine, S., Ogino, K., Kawamura, Y., Dohi, T., Fujimoto, M., Sasazuki, T. Dermatitis due to epiregulin deficiency and a critical role of epiregulin in immune-related responses of keratinocyte and macrophage. Proc. Nat. Acad. Sci. 101: 13921-13926, 2004. [PubMed: 15365177] [Full Text: https://doi.org/10.1073/pnas.0404217101]
Takahashi, M., Hayashi, K., Yoshida, K., Ohkawa, Y., Komurasaki, T., Kitabatake, A., Ogawa, A., Nishida, W., Yano, M., Monden, M., Sobue, K. Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells. Circulation 108: 2524-2529, 2003. [PubMed: 14581411] [Full Text: https://doi.org/10.1161/01.CIR.0000096482.02567.8C]
Toyoda, H., Komurasaki, T., Uchida, D., Morimoto, S. Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family. Biochem. J. 326: 69-75, 1997. [PubMed: 9337852] [Full Text: https://doi.org/10.1042/bj3260069]
Toyoda, H., Komurasaki, T., Uchida, D., Takayama, Y., Isobe, T., Okuyama, T., Hanada, K. Epiregulin: a novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J. Biol. Chem. 270: 7495-7500, 1995. [PubMed: 7706296] [Full Text: https://doi.org/10.1074/jbc.270.13.7495]