Unipotent mammary myoepithelial progenitor cells terminal...

Unipotent mammary myoepithelial progenitor cells terminally differentiate into myoepithelial cells, which are located between luminal cells that line the mammary ducts and alveoli, and the basement membrane (reviewed in Stingl et al. 2005). Myoepithelial cells form a continuous sheath around the ducts but are sparser around the alveoli, where their cytoplasmic processes create a basket-like structure that allows some luminal cells to come in contact with the basement membrane (reviewed in Stingl et al. 2005). Myoepithelial cells are spindle shaped and are able to contract in response to oxytocin, which is necessary for milk secretion (lactation) (reviewed in Stingl et al. 2005, and Watson and Khaled 2020). Markers of human mammary myoepithelial cells are listed in the table below (in the table, "No" means that the marker is not listed for the specified cell type while "N/A" means that the specified cell type is not annoted in the cited external marker database).

EGFR ligands EGF and TGFA stimulate differentiation of the myoepithelial cell lineage (Pasic et al. 2011, Mukhopadhyay et al. 2013). EGF and especially TGFA stimulate prolonged and more intensive EGFR and downstream RAS/RAF/MAPK and PI3K/AKT signaling, and RAS/RAF/MAPK signaling in particular is necessary for the differentiation of the myoepithelial lineage (Pasic et a. 2011, Mukhopadhyay et al. 2013).

Complete loss of EPCAM protein, which is expressed at a low level in myoepithelial progenitor cells, is associated with terminal differentiation of mammary myoepithelial cells (Stingl et al. 2001).

As opposed to luminal cells, myoepithelial cells show limited expression of progesterone and estrogen receptors. A study by Hilton et al. 2012 reported that myoepithelial cells did not express progesterone receptor (PGR), and that PGR was exclusively expressed by luminal cells. A study by Taylor et al. 2009 reported that myoepithelial cells did not express the splicing isoform A of PGR (known as PGR-A or PRA), but a small percentage of myoepithelial cells expressed the splicing isoform B (known as PGR-B or PRB). Both PGR-A and PGR-B are expressed by luminal cells (Taylor et al. 2009). Estrogen receptor alpha (known as ER-alpha or, officially, ESR1), expressed in luminal cells, is not expressed in myoepithelial cells (Taylor et al. 2009).

KRT5 protein, while detectable in the basal/myoepithelial layer of normal adult human breast tissue (Bocker et al. 1992), is expressed only in MaSC-like cells and immature myoepithelial cells/myoepithelial progenitors and not present in fully differentiated myoepithelial cells (Bocker et al. 2002, Boecker et al. 2002, Zhao et al. 2010, Zhao et al. 2012, Mukhopadhyay et al. 2013). Similarly, findings in myoepithelial progenitors derived in vitro from immortalized human mammary epithelial cells suggest that levels of ITGA6, KRT14 and TP63 progressively decrease from the MaSC through the myoepithelial progenitor state and that at later cell divisions of myoepithelial progenitors expression of these markers may become undetectable (Zhao et al. 2012). The majority of studies, however, show that KRT14 continues to be expressed in mature myoepithelial cells, which is supported by the study of human mammary organoids grown from primary, non-transformed human mammary epithelial cells (Pasic et al. 2011). The study by Pasic et al. 2011 supports the decline of TP63 and ITGA6 expression in the majority of mature myoepithelial cells, so that in human mammary organoids they remain detectable only in peripheral myoepithelial cells that are in contact with matrigel, suggesting that sustained TP63 expression may require integrin signaling (Pasic et al. 2011). TP63 and ITGA6 are therefore not annotated as markers of mature, terminally differentiated mammary myoepithelial cells. Vimentin (VIM) was reported to be expressed in myoepithelial cells of normal adult human breast (Bocker et al. 1992). As VIM is, however, associated with myoepithelial progenitor cell phenotype in the majority of studies, it has not been annotated as a marker.

The expressed splicing isoforms of MYH11 (myosin heavy chain 11), which, together with ACTA2 and calponin (reviewed in Dewar et al. 2011) is part of contractile apparatus that enables milk secretion (lactation) in response to oxytocin, differ between myoepithelial cells of non-lactating and lactating human breasts (Ohyabu et al. 1998).

While both MME and MYH11 immunohistochemical staining are used to distinguish benign from malignant breast lesions, MYH11 is more sensitive and specific (Kalof et al. 2004, reviewed in Dewar et al. 2011).

Expression of CDH3 (Cadherin-3, also known as P-cadherin) is increased in benign and malignant breast lesions compared to myoepithelial cells of normal breasts (Palacios et al. 1995, Glukhova et al. 1995, Turashvili et al. 2011). In lactating breasts, CDH3 was reported to be secreted (Soler et al. 2002).