This is a resubmission of a competing renewal application of a research program currently in its 41st year of funding that has been supported previously by two MERIT awards. The long-term objectives of these studies have been to elucidate the mechanisms by which systemic hormones and local growth factors regulate the normal development of the mammary gland, and to determine how these regulatory mechanisms have deviated in breast cancer. A hierarchy of epithelial subsets, spanning stem cells to more differentiated progeny relies on paracrine cues downstream of steroid hormones to provide a mechanism of signaling refinement. However, the hierarchical relationships between different subsets of mammary stem cells, their lineage commitment and the underlying pathways regulating these fate decisions remain poorly understood. The progress made in the previous 5-year cycle identified the functional importance of two critical paracrine mediators of steroid hormone action, Wnt and FGF pathways, in normal mammary stem cells and cancer stem cells, the cooperatively between these two pathways, and their clinical relevance in breast cancer. With Wnt and FGF signaling as the central focus of the current proposal, we will further investigate and illuminate novel functions for these pathways specifically in 1) regulating cell fate and lineage specification in mammary gland development and 2) translational control of novel mediators during breast cancer initiation. Intrinsic subtypes of breast cancer share striking similarity to the differentiation states of the normal mammary epithelial hierarchy, so deciphering these regulatory mechanisms should help provide a better understanding of complex cellular interactions in breast cancer. We hypothesize that Wnt and FGF pathways provide fundamental cellular cues that guide decisions of self-renewal and proliferation, respectively, instrumental for cell fate specification and lineage commitment during mammary development and breast cancer initiation. We propose to 1) To elucidate the mechanisms by which canonical Wnt pathway-responsive stem cells maintain homeostasis and specify the basal cell lineage in the mammary gland during a critical and highly dynamic developmental window, and 2) To decipher the mechanisms of Wnt and Fgf cooperativity on translational regulation of several lncRNAs, and the importance of this translational control in early breast cancer initiation. The current proposal will implement gain- and loss-of-function mouse genetic experiments, lentiviral-based strategies of transplanted epithelial cells in vivo for pathway assessment in situ, and lineage-tracing approaches to address many fundamental questions related to Wnt and Fgf biology. Our studies underscore the necessity for the continued investigation and identification of novel mechanisms regulating normal mammary gland homeostasis and the value of developmental biology in deciphering aspects of cancer biology.
Approximately 1 in 8 women will be stricken by breast cancer in their lifetime. Discovering the mechanisms by which hormones and local growth factors regulate normal mammary stem and progenitor cells will be critical to our understanding of the alterations which occur both during both the initiation of breast cancer, as well as during cancer metastasis and disease recurrence.
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