Transcriptional regulators in mammary gland development and cancer

Abstract

The mammary gland represents a remarkable developmental system for the study of genetic programs underlying proliferation, differentiation and inductive tissue interactions. Mammary gland ontogeny occurs predominantly in the adult and involves a complex cycle of morphogenesis, with the continuous production, differentiation and apoptosis of mammary epithelial cells occurring with each pregnancy. Perturbations in pathways controlling any of these processes may lead to neoplasia. Substantial progress has been made in defining signaling pathways important for mammopoiesis, in particular those that mediate the effects of peptide and steroid hormones. However, much less is known about the transcriptional regulators that dictate cell specificity, proliferation and differentiation within the mammary gland. This review will discuss recent insights into the transcriptional networks important for mammary gland development and consider how deregulation of specific transcription factors contributes to the pathogenesis of breast cancer.

Introduction

A central question in developmental biology is the nature of the transcriptional circuitry that controls cell-fate determination and differentiation in a given organ or tissue. Transcription factors have been shown to have critical roles in numerous cellular systems, using targeted gene deletion together with gain-of-function studies. For example, MyoD, SCL, NeuroD, and Nkx2.5 have essential roles in muscle, hemopoietic, neuronal and heart development, respectively (Biben, Palmer, Elliott, & Harvey, 1997; Massari & Murre, 2000; Weintraub et al., 1991). Although some transcriptional regulators are restricted to specific lineages, most are expressed in multiple lineages and in several different organs. Within breast tissue, few cell-restricted transcription factors have been identified. While the estrogen and progesterone steroid hormone receptors display restricted expression profiles, the majority of regulators are also found in several tissues outside of this organ. It therefore appears likely that these transcription factors serve more than one function through their combinatorial association with distinct proteins in different cell types (Table 1).

Over the past few years, significant new insights have been made in our understanding of transcription factors and cofactors that guide development in the mammary gland. This review will highlight key nuclear regulatory proteins, many of which have been established to have critical roles in the mammary gland through their targeted deletion. Some of these transcription factors, upon deregulation, have been implicated in breast oncogenesis. We will discuss potential targets and mechanisms by which these factors may perturb normal breast epithelial cell development.