Our understanding of the mechanism of cancer dormancy is emerging, but the underlying mechanisms are not fully understood. Here we analyzed mouse xenograft tumors derived from human breast cancer tissue and the human breast cancer cell line MDA-MB-231 to identify the molecules associated with cancer dormancy. In immunohistological examination using the proliferation marker Ki-67, the tumors included both proliferating and dormant cancer cells, but the number of dormant cells was remarkably increased when they metastasized to the lung. In the gene expression analysis of the orthotopic cancer cells by a single-cell multiplex real-time quantitative reverse transcription PCR followed by flow cytometric analysis, restrained cellular proliferation was associated with downregulation of the chemokine receptor CXCR4. In the immunohistological and flow cytometric analyses, the expression level of CXCR4 in the metastasized cancer cells was decreased compared with that in the cancer cells in orthotopic tumors, although the expression level of the CXCR4 ligand CXCL12 was not reduced in the lung. In addition, the proliferation of the metastasized cancer cells was further decreased by the CXCR4 antagonist administration. In the ex vivo culture of the metastasized cancer cells, the expression level of CXCR4 was increased, and in the xenotransplantation of ex vivo cultured cancer cells, the expression level of CXCR4 was again decreased in the metastasized cancer cells in the lung. These findings indicate that CXCR4 is downregulated in metastasized breast cancer cells and implicated in their dormancy.

Mammary gland development is induced by the actions of various hormones to form a structure consisting of collecting ducts and milk-secreting alveoli, which comprise two types of epithelial cells known as luminal and basal cells. These cells adhere to each other by cell adhesion apparatuses whose roles in hormone-dependent mammary gland development remain largely unknown. Here we identified a novel cell adhesion apparatus at the boundary between the luminal and basal cells in addition to desmosomes. This apparatus was formed by the trans-interaction between the cell adhesion molecules nectin-4 and nectin-1, which were expressed in the luminal and basal cells, respectively. Nectin-4 of this apparatus further cis-interacted with the prolactin receptor in the luminal cells to enhance the prolactin-induced prolactin receptor signaling for alveolar development with lactogenic differentiation. Thus, a novel nectin-mediated cell adhesion apparatus regulates the prolactin receptor signaling for mammary gland development.The adult mammary gland, consisting of collecting ducts and alveoli, is arranged in a bi-layer structure of inner luminal cells surrounded by basal myoepithelial cells, with the outermost side ensheathed by the basement membrane (1) (Fig. 1A). The luminal cells form a sheet by adhering to adjacent cells through cell adhesion apparatuses, including tight junctions (TJs), These cell adhesion apparatuses are composed of cell adhesion molecules (CAMs) and peripheral membrane proteins, which connect CAMs with cytoskeletal proteins, such as actin filaments (F-actin), intermediate filaments, and microtubules (5, 6). The major CAMs at AJs are classical cadherins and nectins (5, 6). Cadherins directly bind ␤-catenin, which interacts with ␣-catenin and is associated with F-actin, whereas nectins bind afadin and are associated with F-actin. The major CAMs at TJs are claudins, occludin, and junctional adhesion molecules (7). These CAMs bind zonula occludens (ZO)-1, ZO-2, and ZO-3 and are associated with F-actin. The major CAMs at desmosomes are desmosomal cadherins, which bind to plakoglobin and plakophilin and are associated with keratin intermediate filaments through desmoplakin (8). Gap junctions consist of connexons made up of six connexin proteins (9). In the mammary gland, these CAMs and their associated molecules have been identified and characterized (10), but nectins and afadin have not yet been investigated.The mammary gland develops from a thickening in the ventral skin during embryogenesis that grows into a rudimentary ductal tree before birth (11-13). The female mammary gland continues to develop in a hormone-independent manner until puberty following which hormones induce ductal elongation and branching. Elongation and branching of ducts along with alveolar development with lactogenic differentiation are induced by pregnancy. This development of the mammary gland during puberty and pregnancy are regulated by hormones, including estrogen, progesterone, and prolactin, and growth factors and cytokines, su...

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