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      Positional Variations in Mammary Gland Development and Cancer

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          Abstract

          Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and the same functional outcome as a milk-producing organ, the mammary glands are easily presumed to be mere copies of one another. Based on our analysis of published data with inclusion of new results related to mammary development and pathology in mice, we argue that this presumption is incorrect: Between and within pairs, mammary glands differ from one another, and tumor incidence and biology depend on the position along the anterior-posterior and the left-right axis as well. This insight has implications for experimental designs with mouse models and for data extrapolation between mammary glands within and between species. We suggest that improved documentation of location-specific mammary gland features will lead to more insights into the molecular mechanisms of mammary gland development and cancer biology in both mice and humans.

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          Most cited references76

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          p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

          The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.
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            p63 is a p53 homologue required for limb and epidermal morphogenesis.

            The p53 tumour suppressor is a transcription factor that regulates the progression of the cell through its cycle and cell death (apoptosis) in response to environmental stimuli such as DNA damage and hypoxia. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known and here we describe the function of p63 in vivo. Mice lacking p63 are born alive but have striking developmental defects. Their limbs are absent or truncated, defects that are caused by a failure of the apical ectodermal ridge to differentiate. The skin of p63-deficient mice does not progress past an early developmental stage: it lacks stratification and does not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth and mammary glands, are absent in p63-deficient mice. Thus, in contrast to p53, p63 is essential for several aspects of ectodermal differentiation during embryogenesis.
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              The Hox genes and their roles in oncogenesis.

              Hox genes, a highly conserved subgroup of the homeobox superfamily, have crucial roles in development, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrations in Hox gene expression have been reported in abnormal development and malignancy, indicating that altered expression of Hox genes could be important for both oncogenesis and tumour suppression, depending on context. Therefore, Hox gene expression could be important in diagnosis and therapy.
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                Author and article information

                Contributors
                jveltmaat.sc@gmail.com
                ramsdell@musc.edu
                sternecg@mail.nih.gov
                Journal
                J Mammary Gland Biol Neoplasia
                J Mammary Gland Biol Neoplasia
                Journal of Mammary Gland Biology and Neoplasia
                Springer US (Boston )
                1083-3021
                1573-7039
                12 May 2013
                12 May 2013
                June 2013
                : 18
                : 2
                : 179-188
                Affiliations
                [ ]Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Singapore, 138673 Singapore
                [ ]Department of Cell Biology and Anatomy and Program in Women’s and Gender Studies, College of Arts and Sciences, University of South Carolina School of Medicine, Columbia, SC 29208 USA
                [ ]Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB Room 601, Charleston, SC 29425 USA
                [ ]National Cancer Institute, Center for Cancer Research, PO Box B, Frederick, MD 21702-1201 USA
                Article
                9287
                10.1007/s10911-013-9287-3
                3691492
                23666389
                50faeb72-9a3f-4502-9da0-a2bf485c7189
                © Springer Science+Business Media New York (outside the USA) 2013
                History
                : 10 March 2013
                : 26 April 2013
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media New York 2013

                Oncology & Radiotherapy
                embryonic development,body axis,anterior-posterior,asymmetry,mammary gland,breast cancer

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