Introduction Cumulative lifetime hormone exposure as a resul

Introduction Cumulative lifetime hormone exposure as a result of natural menstrual cycles and exogenous hormone therapies is a strong determinant of increased breast cancer risk. Progesterone, an ovarian steroid hormone that peaks during the luteal phase of the menstrual cycle, promotes the expansion of stem and progenitor formyl peptide receptors in the mammary gland (Joshi et al., 2010, 2012). Given their multipotency, self-renewal, proliferative properties, and shared molecular signatures with specific breast cancer subtypes, mammary stem and progenitor cells have been proposed to be cellular targets of transformation in breast cancer (Visvader, 2011). Since hormones play an integral role in breast cancer development and stem cell control, an in-depth understanding of the mechanisms responsible for hormone action on distinct cell types in the mammary gland is highly warranted. Through global transcriptomic analyses of purified mammary epithelial subsets (basal, luminal, and stromal) followed by phenotypic and functional studies, we identify and validate CXCR4 as a critical mediator of progesterone signaling in the adult mammary gland. CXCR4, together with its ligand, CXCL12, is well known for its role in regulating the migration of hematopoietic stem cells to the bone marrow, and controlling their quiescence, proliferation, and recruitment to the circulation (Honczarenko et al., 2006; Lapidot and Kollet, 2002). Further, CXCR4 and CXCL12 promote metastasis in several cancers, including breast cancer, where they are associated with tamoxifen resistance and poor prognosis (Mukherjee and Zhao, 2013). Our study reveals a previously uncharacterized nexus between CXCR4 and progesterone signaling that drives the recruitment of mammary stem and progenitor cells during epithelial expansion and lobuloalveolar regeneration.
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Introduction Complex multicellular organisms contain a wide spatial and temporal diversity of cell types. Gene expression and signaling mechanisms are tightly coordinated processes that are recycled throughout development, maturation, and aging, thus maintaining a smaller overall gene number. This makes the investigation of gene function dependent on the ability to precisely manipulate gene expression in each spatial and temporal context. In the CNS, one such example is the Notch signaling pathway, which is involved in a multitude of cell types from development to late neurodegeneration (Ables et al., 2011). The dynamic cellular contexts and diverse signaling interactions create the need to temporally regulate gene activity in order to precisely study gene function. Moreover, transgene manipulation has emerged as an important technique to study and treat disease. Specifically, directing neuronal subtype differentiation is important for disease modeling, and regulated growth factor secretion is a promising therapy for several neurodegenerative diseases (Behrstock et al., 2006; Marchetto et al., 2011). Tetracycline (Tet)-regulated systems have been used to temporally and spatially regulate gene expression in various methodologies (Furth et al., 1994; Gossen and Bujard, 1992). Specifically, the bacterial Tet transactivator (tTA) has been optimized to silence gene expression downstream of a Tet-regulated promoter in the presence of doxycycline (dox), a Tet analog. In addition to this “Tet-Off” system, a “Tet-On” system uses a reverse tTA (rtTA) in order to activate transgene expression in the presence of dox (Mansuy and Bujard, 2000). Tet-inducible systems have suffered from “leaky” gene expression and low inducibility of transgene expression over baseline (Mansuy and Bujard, 2000). These drawbacks, along with epigenetic silencing of these elements through endogenous methylation, contribute to the limitations related to CNS transgene regulation (Zhu et al., 2007). While new tTA and rtTA variants help overcome some of these limitations (Zhou et al., 2006), their use in neural stem cell populations is unexplored.