EGF family

Epidermal growth factor (EGF) was discovered by accident in the 1960s when unexpected biological activity (not attributed to nerve growth factor) occurred following injections of extracts of murine salivary glands into test animals.

This family of proteins contains at least ten members including: EGF, heparin-binding EGF, transforming growth factor a (TGF-θc), amphiregulin, neuroregulins (four subtypes), and several heregulins.

Dysfunction of these receptors is common in many forms of carcinogenesis, which explains much of the emphasis for work in this area. A direct connection between the ErbB family and cancer was established with the breakthrough that the retroviral oncogene V-ErbB, which is transduced by the avian erythroblas­tosis virus, is a form of an avian EGF receptor. This then led to subsequent discoveries showing that over­expression of ErbB agonist proteins and/or overex­pression or inappropriate expression of ErbB receptors were important in a variety of human cancers. In fact, a humanized monoclonal antibody against ErbB-2 called Herceptin was the first such product approved for human use. It was designed specifically for breast cancer patients with tumors that overexpress ErbB-2 (Harris et al., 2003; Stern, 2003).

EGF is important in normal mammary gland devel­opment in mice and likely other species as well. In particular, there is compelling evidence to suggest that estrogen (a potent mammogenic hormone from the ovary) likely induces local production of EGF agonists (EGF itself, TGFoc, or amphiregulin) and that these agents are important in alveolar development.

For tissues that synthesize EGF or its related ligands, these growth factors are made as transmembrane gly­coproteins. The EGF-Iike sequences are external to the

Fig. 12.39. Panel A illustrates a concentration depending increase in mammary cell proliferation (% epithelial cell nuclei labeled with tritiated thymidine). Panel B illustrates that addition of EGF can have lactogenic effects on bovine mammary tissue as evidenced by an increase the secretion of the milk protein (α-S₁ casein) by mammary explants from mid-gestation heifer culture. This lactogenic response is similar to responses following addition of bovine prolactin or human growth hormone. Interestingly, addition of EGF did not increase secretion of the milk protein Oi-Iactalbumin as did addition of both bPrl and hGH.

plasma membrane. Requirements for secretion are not completely understood but involve the action of a pro­tease that cleaves the membrane-bound protein for release of the EGF (or relative) into the interstitial fluid. Induced overexpression of TGF-Ot under control of mammary promoters in rodents leads to the appear­ance of mammary tumors. This fits with measure­ments showing that some spontaneous human mammary tumors also express large amounts of TGF-OC or EGF receptor. It is also important to remem­ber that responses of cells or tissues in culture may not necessarily reflect the response of tissue in the complex environment of the intact animal. Presence of EGF receptors and ligands and demonstrated response of ruminant mammary cells to EGF support a role for these growth factors in mammogenesis, but much more information is needed to determine exact roles. In short, it is not known if the EGF family of proteins and receptors is largely permissive or if they have an essential direct impact in ruminant mammary development.

The EGF family is also important in the growth and development of hair, so there is much interest in impacts of these growth factors on wool and other animal hair products. Specifically, the hair follicle has two closely aligned epithelial cell layers. The inner root sheath cells produce TGF-α but do not express EGF receptor (ErbB-I), but the opposite is true for the outer root sheath (receptors but no TGF-α). For normal growth it is essential that newly formed TGF-OC be processed for release and then rapidly bound by receptors in the outer sheath of cells. In the case of EGFR- or TGF-0C-null mice, which are engineered without the receptor and/or ligand, hair follicle for­mation is disturbed. When this local TGF-oc escapes capture, it acts an attractor of other cells into the region of the hair follicle so that the hair coat is abnormal and whiskers are wavy (Mann et al., 1993).