دورية أكاديمية
ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.
| العنوان: | ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation. |
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| المؤلفون: | Williams MM; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Vaught DB; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Joly MM; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Hicks DJ; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Sanchez V; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Owens P; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Rahman B; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Elion DL; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA., Balko JM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Cook RS; Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA. Rebecca.cook@vanderbilt.edu. |
| المصدر: | Breast cancer research : BCR [Breast Cancer Res] 2017 Sep 08; Vol. 19 (1), pp. 105. Date of Electronic Publication: 2017 Sep 08. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London, UK : BioMed Central Ltd Original Publication: London, UK : Current Science, c1999- |
| مواضيع طبية MeSH: | Breast/*cytology , Breast/*metabolism , Cell Differentiation/*genetics , Epithelial Cells/*cytology , Epithelial Cells/*metabolism , Lactation/*genetics , Receptor, ErbB-3/*genetics, Alleles ; Animals ; Cell Proliferation/genetics ; Cell Survival/genetics ; Female ; Gene Knockout Techniques ; Immunohistochemistry ; Mice ; Mice, Transgenic ; Phosphatidylinositol 3-Kinases/metabolism ; Pregnancy ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptor, ErbB-3/metabolism ; Receptor, ErbB-4/genetics ; Receptor, ErbB-4/metabolism ; STAT5 Transcription Factor/metabolism ; Signal Transduction |
| مستخلص: | Background: During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland. Methods: We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs). Results: Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 KO dams weighed significantly less when compared to litters nursed by ErbB3 WT dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 KO samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 KO aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 KO MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 KO mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype. Conclusions: These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation. |
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| معلومات مُعتمدة: | UL1 TR000445 United States TR NCATS NIH HHS; R13 TR000044 United States TR NCATS NIH HHS; F31 CA195989 United States CA NCI NIH HHS; P30 CA068485 United States CA NCI NIH HHS; U13 TR000044 United States TR NCATS NIH HHS; P50 CA098131 United States CA NCI NIH HHS; R25 GM062459 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Akt; Alveolar mammary epithelial cell; ErbB3; ErbB4; Jak2; Lactation; Mammary gland development; PI3 kinase; Prolactin; STAT5A |
| المشرفين على المادة: | 0 (RNA, Messenger) 0 (STAT5 Transcription Factor) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.10.1 (Receptor, ErbB-3) EC 2.7.10.1 (Receptor, ErbB-4) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) |
| تواريخ الأحداث: | Date Created: 20170910 Date Completed: 20180511 Latest Revision: 20230808 |
| رمز التحديث: | 20230808 |
| مُعرف محوري في PubMed: | PMC5591538 |
| DOI: | 10.1186/s13058-017-0893-7 |
| PMID: | 28886748 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1465-542X |
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| DOI: | 10.1186/s13058-017-0893-7 |