The research objectives of my laboratory are to elucidate the mechanisms regulating the normal development of the mammary gland including the hormonal control of milk protein gene expression, and to determine how these regulatory mechanisms have deviated in breast cancer.
In the mouse mammary gland, there are several critical periods of development; ductal proliferation and branching that occur during sexual maturity, lobuloalveolar proliferation that occurs during pregnancy, terminal differentiation and lactation, and involution characterized by increased apoptosis and extensive tissue remodeling.
Our laboratory is studying the role of systemic hormones, specifically prolactin, glucocorticoids, estrogens and progestins, and local growth factors, including members of the Wnt, Fgf and IGF families, on these processes. The role of specific transcription factors and their dominant-negative isoforms, including members of the C/EBP, Stat and NF I families, are also being examined using transgenic and knockout mouse models.
Gene arrays and subtractive hybridization techniques are being employed to identify downstream targets of these transcription factors. Postnatal mammary gland development is being studied in knockout mice displaying late embryonic or neonatal mortality by transplantation of mammary epithelium into the cleared mammary gland fat pad of syngeneic recipients.
Genetically engineered mice, coupled with FACS analysis and transplantation into the cleared mammary fat pad, have also been employed as model system in which to isolate and characterize functional mammary progenitors and stem cells.
Finally, transgenic and knockout mouse models are being used to elucidate changes in normal mammary gland stem cells and progenitors and signal transduction pathways that are involved in the progression from the normal mammary gland to preneoplasias, as well as the role of mutant p53 and Chk1 in genomic instability and the development of aneuploidy.
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