PMID- 24124521 OWN - NLM STAT- MEDLINE DCOM- 20140711 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 10 DP - 2013 TI - Distinct effects of EGFR ligands on human mammary epithelial cell differentiation. PG - e75907 LID - 10.1371/journal.pone.0075907 [doi] LID - e75907 AB - Based on gene expression patterns, breast cancers can be divided into subtypes that closely resemble various developmental stages of normal mammary epithelial cells (MECs). Thus, understanding molecular mechanisms of MEC development is expected to provide critical insights into initiation and progression of breast cancer. Epidermal growth factor receptor (EGFR) and its ligands play essential roles in normal and pathological mammary gland. Signals through EGFR is required for normal mammary gland development. Ligands for EGFR are over-expressed in a significant proportion of breast cancers, and elevated expression of EGFR is associated with poorer clinical outcome. In the present study, we examined the effect of signals through EGFR on MEC differentiation using the human telomerase reverse transcriptase (hTERT)-immortalized human stem/progenitor MECs which express cytokeratin 5 but lack cytokeratin 19 (K5(+)K19(-) hMECs). As reported previously, these cells can be induced to differentiate into luminal and myoepithelial cells under appropriate culture conditions. K5(+)K19(-) hMECs acquired distinct cell fates in response to EGFR ligands epidermal growth factor (EGF), amphiregulin (AREG) and transforming growth factor alpha (TGFalpha) in differentiation-promoting MEGM medium. Specifically, presence of EGF during in vitro differentiation supported development into both luminal and myoepithelial lineages, whereas cells differentiated only towards luminal lineage when EGF was replaced with AREG. In contrast, substitution with TGFalpha led to differentiation only into myoepithelial lineage. Chemical inhibition of the MEK-Erk pathway, but not the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, interfered with K5(+)K19(-) hMEC differentiation. The present data validate the utility of the K5(+)K19(-) hMEC cells for modeling key features of human MEC differentiation. This system should be useful in studying molecular/biochemical mechanisms of human MEC differentiation. FAU - Mukhopadhyay, Chandrani AU - Mukhopadhyay C AD - Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. FAU - Zhao, Xiangshan AU - Zhao X FAU - Maroni, Dulce AU - Maroni D FAU - Band, Vimla AU - Band V FAU - Naramura, Mayumi AU - Naramura M LA - eng GR - R01 CA096844/CA/NCI NIH HHS/United States GR - R01 CA144027/CA/NCI NIH HHS/United States GR - CA144027/CA/NCI NIH HHS/United States GR - CA96844/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20131004 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Transforming Growth Factor alpha) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Amphiregulin MH - Cell Differentiation/genetics/*physiology MH - Cell Line MH - EGF Family of Proteins MH - Epidermal Growth Factor/pharmacology MH - Epithelial Cells MH - ErbB Receptors/agonists/*metabolism MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Glycoproteins/pharmacology MH - Humans MH - Immunoblotting MH - Intercellular Signaling Peptides and Proteins/pharmacology MH - Mammary Glands, Human/*cytology MH - Microscopy, Confocal MH - Transforming Growth Factor alpha/pharmacology PMC - PMC3790811 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2013/10/15 06:00 MHDA- 2014/07/12 06:00 PMCR- 2013/10/04 CRDT- 2013/10/15 06:00 PHST- 2013/05/06 00:00 [received] PHST- 2013/08/16 00:00 [accepted] PHST- 2013/10/15 06:00 [entrez] PHST- 2013/10/15 06:00 [pubmed] PHST- 2014/07/12 06:00 [medline] PHST- 2013/10/04 00:00 [pmc-release] AID - PONE-D-13-18673 [pii] AID - 10.1371/journal.pone.0075907 [doi] PST - epublish SO - PLoS One. 2013 Oct 4;8(10):e75907. doi: 10.1371/journal.pone.0075907. eCollection 2013.