The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini.
We have utilized in vitro three-dimensional epithelial cell cultures to analyze the role of apoptosis in the formation and maintenance of a hollow glandular architecture. Lumen formation is associated with the selective apoptosis of centrally located cells; this apoptosis follows apicobasal polarization and precedes proliferative suppression during acinar development. Notably, either inhibiting apoptosis (by exogenously expressing antiapoptotic Bcl family proteins) or enhancing proliferation (via Cyclin D1 or HPV E7 overexpression) does not result in luminal filling, suggesting glandular architecture is resistant to such isolated oncogenic insults. However, the lumen is filled when oncogenes that enhance proliferation are coexpressed with those that inhibit apoptosis, or when ErbB2, which induces both activities, is activated by homodimerization. Hence, apoptosis can counteract increased proliferation to maintain luminal space, suggesting that tumor cells must restrain apoptosis to populate the lumen.
Debnath
Jayanta
J
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Mills
Kenna R
KR
Collins
Nicole L
NL
Reginato
Mauricio J
MJ
Muthuswamy
Senthil K
SK
Brugge
Joan S
JS
D000199:Actins / Q000378:metabolism; D000925:Anticoagulants / Q000494:pharmacology; D017209:Apoptosis; D001672:Biocompatible Materials / Q000494:pharmacology; D001940:Breast / Q000378:metabolism* / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D002455:Cell Division; D003094:Collagen / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D003911:Dextrans / Q000494:pharmacology; D004338:Drug Combinations; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000199:Actins; D000925:Anticoagulants; D001672:Biocompatible Materials; D003094:Collagen; D019938:Cyclin D1; D003911:Dextrans; D004338:Drug Combinations; D019394:Ki-67 Antigen; D007797:Laminin; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; C059731:oncogene protein E7, Human papillomavirus type 16; C059485:matrigel