Adult stem cells are thought to be long-lived, primarily quiescent cells that undergo asymmetric and occasionally symmetric cell division to self-renew, maintaining a stem cell pool, and differentiate into more committed cells which replenish their particular tissue.  These cellular functions are regulated by signals, either secreted factors or cell-cell interactions, provided in the local stem cell microenvironment referred to as the stem cell niche.  Direct evidence for the existence of mammary gland stem cells has accumulated over the past several decades.  Studies have shown the transplantation of random fragments of mammary tissue into the cleared mammary fat pad of recipient mice are capable of growing into all cell types of a functional mammary gland.  However, the precise location and characterization of the stem niche have not been determined in the mammary gland.

  Stem cells have long been hypothesized to be the cellular origin of cancer.  Recently, this assertion has been supported by the reconstitution of tumors after several rounds of serial transplantation in leukemia, brain and breast cancers.  Several investigators have employed a variety of methods to identify mammary stem cells including electron microscopy, non-adherent mammosphere cultures, and flow cytometry.  However, these studies have not allowed the isolation and detailed characterization of quiescent stem cells present in the niche, or determined the localization of the stem cell niche within the mammary gland.

The objectives of my studies are to localize the stem cell niche within the normal mammary gland and within mammary tumors to determine the alterations in regulatory mechanisms leading to tumor initiation.  Specifically, to identify unique surface markers which define mammary stem cells and breast cancer stem cells, to identify niche support cells directly interacting with stem cells, and elucidate the mechanisms that regulate stem cell self-renewal and differentiation in mouse models. We hypothesize that alterations in mechanisms regulating self-renewal and differentiation in long-term mammary gland stem cells initiate the development of breast cancer.