Abstract
Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is a morphogen in an in vitro model for lumen formation and plays a similar role in breast epithelial cells implanted in humanized mammary fat pads in NOD-SCID mice. Although extra cellular matrix alone is sufficient to stimulate lumen formation in CEACAM1 transfected MCF-7 cells grown in 3D culture, there is an additional requirement for stromal or mesenchymal cells (MSCs) for these cells to form xenografts with glandular structures in an orthotopic site. We demonstrate that optimal in vitro conditions include both Matrigel and MSCs and that the inclusion of collagen I inhibits xenograft differentiation. Additionally, there is no need to remove the nascent murine mammary gland. The previously observed difference in gland development between the long and short cytoplasmic domain isoforms of CEACAM1 is no longer observed in pregnant NOD/SCID mice suggesting that stimulation of the mammary fat pad by pregnancy critically affects xenograft differentiation.
Highlights
Mammary gland development is critically dependent on mesenchymal tissue [1, 2]
We utilized wild type or Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1)-4S transfected MCF7 (MCF7/CEACAM1) cells implanted as a single cell suspension rather than as mammospheres because we felt that the preformation of mammospheres may already resemble gland formation
Considerable progress has been made in the development of an in vitro 3D model of human mammary morphogenesis, the 3D model lacks the physiological setting of a live animal that includes features such as the cellular components of the immune system and angiogenesis, or hormonal influences from the endocrine glands, ovary, and the mammary gland itself
Summary
Mammary gland development is critically dependent on mesenchymal tissue [1, 2]. In the correct context, mammary epithelial cells will develop branched glandular tissue capable of milk production. The identification of essential components for proper growth of breast cancer epithelial cells was pioneered by Bissell and coworkers in an in vitro model in which mammary epithelial cells are grown in a 3D culture of extracellular matrix supplied by Matrigel [3, 4] This model lacks the contribution of mesenchymal cells (MSCs) that are implicated in both normal mammary gland development and breast cancer [1, 5]. We found a difference in gland formation between the two major isoforms of CEACAM1, namely, the short (forms no glands) versus the long (forms glands) cytoplasmic domain isoforms This difference has led us to speculate that the ratio of short to long isoforms in human breast may become altered in breast cancer leading to the altered morphology characteristic of ductal carcinoma in situ (DCIS) [9]. These results have prompted us to dissect the phosphorylation status of the long and short cytoplasmic domains in further
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