Transforming growth factor alpha and mouse models of human breast cancer

Abstract

Transforming growth factor alpha (TGFa) is a principal molecule in the normal and neoplastic development of the mammary gland. Binding of TGFa to the epidermal growth factor receptor (EGFR), activates the EGFRs' endogenous tyrosine kinase activity and stimulates growth of the epithelium in the virgin and pregnant mouse mammary gland. TGFa expression can be detected in breast cancer cells in vivo and in vitro and overexpression can elicit partial transformation or immortalized human and rodent mammary epithelial cells. Despite evidence implicating TGFa in the development of mammary neoplasia, the actual mechanism of TGFa-induced transformation is unclear. Transgenic mouse models targeting heterologus TGFa to the mammary gland have established TGFa overexpression can induce hyperproliferation, hyperplasia and occasional carcinoma. These transgenic studies demonstrated a facilitating, proliferative role for TGFa in the development of neoplasia and implicated several oncogenes that can cooperate with TGFa to transform the mammary epithelium. From studies of EGFR signaling pathways, inhibitory and modulating agents such as anti-EGFR antibodies and speci®c kinases inhibitors have been used to block the action of this pathway and prevent the development of TGFa-induced neoplasia and tumor formation. Studies in Stat5a knockout mice have established that the JAK2/Stat5a pathway can facilitate the survival of the mammary epithelium and can impact the progression of TGFa-mandated mammary tumorigenesis. Together these experiments indicate that TGFa and the EGFR signaling pathway are potentially amenable to therapies for treatment of human breast disease.

Transgenic mouse models of human breast cancer

“…The relationship between mammary development and tumorigenesis is highlighted by the observation that these mice also displayed signi®cant delays in mammary gland involution (Sandgren et al, 1995). As these mice still required multiple pregnancies for tumors to form, it is possible that this delay in involution may act to provide an expanded population of proliferating epithelial cells predisposed to transformation (Humphreys and Hennighausen, 2000). However, the long latency observed once again indicates that additional genetic events are necessary for tumor progression in this model.…”

“…TGF-a possesses strong homology to EGF and like EGF acts as a ligand for the EGFR. TGF and EGFR expression has been found to coincide with normal mammary epithelial proliferation in vivo (reviewed in Humphreys and Hennighausen, 2000). Early studies with transgenic mice expressing TGF-a weakly in the mammary gland showed increased cellular proliferation and fat pad developmental defects (Sandgren et al, 1990).…”

Estrogen receptor-positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss

“…Recent findings revealing distinctive molecular profiles for ERÀ tumors containing ErbB1 versus ErbB2 (Creighton et al, 2006) may shed light on these differences. Cystic papillary tumors in NRL-TGFa mice resemble those of other TGFa transgenic mice (Humphreys and Hennighausen, 2000;Rose-Hellekant and Sandgren, 2000;Arendt et al, 2006). Concurrent expression of heterozygous p53 results in aggressive solid tumors of varying types reflecting the tumor spectrum of p53 þ /À BALB/c mice (Blackburn et al, 2003;Jerry et al, 2000;Kuperwasser et al, 2000), although relative proportions cannot be determined due to low numbers of p53 þ /À mice in the present study.…”

“…While TGFa-induced mammary tumorigenesis has been described using the WAP, MMTV and MT promoters (Humphreys and Hennighausen, 2000;Rose-Hellekant and Sandgren, 2000), estrogen sensitivity and/or the expression pattern of these traditional promoters has limited their application. MMTV-transgene expression is uniform at 6 weeks, but becomes focally expressed by 15 weeks (Gunther et al, 2002), and progesterone activates this promoter (Otten et al, 1988).…”

Negative Regulation of HER2 Signaling by the PEST-type Protein-tyrosine Phosphatase BDP1

“…Next we compared the protein level of BDP1 in breast tumors from transgenic mice expressing HER2 or other oncogenes under the control of gene promoters, which restrict oncogene expression to the mammary alveolar epithelium (41)(42)(43)(44)(45). Although BDP1 was readily detected in all samples tested, its expression was maximal in the HER2-overexpressing tumor (Fig.…”