Transgenic models to study actions of prolactin in mammary neoplasia

Abstract

Transgenic models to explore the role of prolactin and its interactions with other factors in mammary oncogenesis have begun to reveal the dynamic contributions of prolactin to the development and progression of this disease. Targeting prolactin to mammary epithelial cells mimics the local production of this hormone that is prominent in women, and permits studies in the absence of effects on the ovarian steroid milieu. These models have demonstrated that local production of prolactin is sufficient to induce mammary tumors after a long latency. Prolactin also can potentiate actions of other oncogenic stimuli, decreasing tumor latency and increasing incidence in several models. Augmented proliferation, without alteration of apoptosis, is a consistent feature. Pathways in addition to the well-characterized Jak2-Stat5 pathway, including ERK1/2 and Akt1/2, are implicated in these actions. These studies have also revealed a complex relationship with estrogen; while prolactin increases ERalpha expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFalpha, prolactin can contribute to estrogen insensitivity. These studies highlight the utility of these models to decipher the interplay between prolactin and other oncogenic factors in breast cancer, with implications for preventative and therapeutic strategies.