Amphiregulin: Role in Mammary Gland Development and Breast Cancer

Abstract

Extensive epithelial cell proliferation underlies the ductal morphogenesis of puberty that generates the mammary tree that will eventually fill the fat pad. This estrogen-dependent process is believed to be essentially dependent on locally produced growth factors that act in a paracrine fashion. EGF-like growth factor ligands, acting through EGF receptors are some of the principal promoters of pubertal ductal morphogenesis. Amphiregulin is the most abundant EGF-like growth factor in the pubertal mammary gland. Its gene is transcriptionally regulated by ERalpha, and recent evidence identifies it as a key mediator of the estrogen-driven epithelial cell proliferation of puberty: The pubertal deficiency in mammary gland ductal morphogenesis in ERalpha, amphiregulin, and EGFR knockout mice phenocopy each other. As a prognostic indicator in human breast cancer, amphiregulin indicates an outcome identical to that predicted by ERalpha presence. Despite this, a range of studies both on preneoplastic human breast tissue and on cell culture based models of breast cancer, suggest a possibly significant role for amphiregulin in driving human breast cancer progression. Here we summarise our current understanding of amphiregulin's contribution to mammary gland development and breast cancer progression.

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

“…During development, amphiregulin is the most abundant epidermal growth factor-like growth factor in the pubertal mammary gland and has an important role in ductal morphogenesis (Luetteke et al, 1999). There is clear evidence for a role of amphiregulin in breast cancer initiation as well as progression (McBryan et al, 2008;Willmarth and Ethier, 2008). Amphiregulin is often overexpressed in mammary carcinoma (Qi et al, 1994) and generally higher in invasive breast carcinomas than in normal mammary epithelium (Panico et al, 1996).…”

FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis

“…Interestingly, TEB development is also disrupted in all of these models. Thus, it is possible that FOXA1 participates in a signaling network that includes one or more of these mediators of breast development and cancer progression (Holbro et al, 2003;McBryan et al, 2008;Wakefield et al, 2001).…”

Hepatitis C virus infection induces the expression of amphiregulin, a factor related to the activation of cellular survival pathways and required for efficient viral assembly

“…AREG mRNA is expressed in many normal tissues, including placenta, testis, pancreas, spleen, kidney, lung, breast, ovary and colon (Plowman et al, 1990). It has been found to play an important role in the mammary gland development, breast cancer and colorectal cancer (Berquin et al, 2001;Bordoli et al, 2010;McBryan et al, 2008;Yotsumoto et al, 2008). Recently, AREG has also been identified as one of the 10-gene signatures in close association with the occurrence of liver metastasis in colorectal cancer patients (Watanabe et al, 2010).…”