Overview
Our research focuses on the initial development of the mammary primordium to determine how undifferentiated tissue is directed to form the mammary gland. The cellular processes that are defective in cancer are in large part those that regulate organ development during embryogenesis. We study early embryonic mammary development to gain a fundamental understanding of the genetic state of the most primitive mammary cells, their interactions, and native functions, to provide insight into the regulation of the processes that occur as the mammary primordium forms (cell adhesion modulation, cell migration, basal proliferation, lineage commitment).
The focus of our research has been on elucidating the genetic basis for mammary gland development. Like many other organs, mammary glands are formed by an exchange of signals between the epithelia and mesenchyme. Unlike other organs, mammary glands continue to develop throughout the life cycle and this development is mediated by the exchange of signals between these two tissues. Our aim is to elucidate the signalling pathways regulating mammary epithelial differentiation. This research focuses on the very early stages of mammary development to determine how undifferentiated tissue is directed to form the mammary primordium during embryogenesis, as this is when the mammary lineage is initially established.
The scaramanga mutation
We have been using mouse models which exhibit abnormal embryonic mammary development to investigate how mammary cell fate is conferred to embryonic cells. The signals that initiate mammary gland formation are not well understood. To better understand these processes we are characterising the scaramanga (ska) mutation, which affects mammary gland development during the initial formation of the mammary primordium.
The ska mutation impairs some of the earliest aspects of mammary gland development. The mammary phenotypes observed in ska mutants are consistent with abnormal inductive events occurring prior to the morphological appearance of the mammary bud. Using a combination of genetic and bioinformatic approaches, we narrowed the genetic interval spanning the ska locus to a size that would aid its identification.
We used positional cloning to identify the gene affected in scaramanga (ska). The ska gene encodes Neuregulin3 (Nrg3), a growth factor, which binds and activates Erbb4, a tyrosine kinase receptor that regulates cell proliferation and differentiation. Nrg3 is a poorly characterised member of an important signalling network. Another member of this signalling family is Erbb2, which has been used successfully as a therapeutic target to development treatment for breast cancer in the form of the drug Herceptin.
Results from tissue recombination experiments suggest that the mesenchyme induces mammary placode formation. Nrg3 is expressed in dermal mesenchyme underlying the sites where the mammary placodes will subsequently form, suggesting an inductive role for Nrg3. Furthermore, Nrg3-soaked beads induce ectopic mammary bud formation in explant cultures. Nrg3, therefore, appears to function as a mesenchymal paracrine signal to regulate epithelial stratification and formation of epithelial aggregations at the sites that mammary primordium form. Expression and functional studies indicate that Nrg3 is a specification signal for mammary glands. We expect further studies will clarify how Nrg3 signalling elicits biological responses in undifferentiated and primitive mammary cells.
We are researching the role of Nrg3 in the determination of mammary epithelial cell fate. Our studies now focus on determining the mechanisms by which Nrg3 as a key component in embryonic mammary specification, elicits mammary morphogenesis and differentiation. We plan to examine how Nrg3 interacts with other signalling pathways relevant to early mammary gland development and cancer. Nrg3 is expressed in some breast cancers but it is not yet known if this expression is clinically relevant.
