Distinct roles of the three Akt isoforms in lactogenic differentiation and involution.
The three Akt isoforms differ in their ability to transduce oncogenic signals initiated by the Neu and PyMT oncogenes in mammary epithelia. As a result, ablation of Akt1 inhibits and ablation of Akt2 accelerates mammary tumor development by both oncogenes, while ablation of Akt3 is phenotypically almost neutral. Since the risk of breast cancer development in humans correlates with multiple late pregnancies, we embarked on a study to determine whether individual Akt isoforms also differ in their ability to transduce hormonal and growth factor signals during pregnancy, lactation and post-lactation involution. The results showed that the ablation of Akt1 delays the differentiation of the mammary epithelia during pregnancy and lactation, and that the ablation of Akt2 has the opposite effect. Finally, ablation of Akt3 results in minor defects, but its phenotype is closer to that of the wild type mice. Whereas the phenotype of the Akt1 ablation is cell autonomous, that of Akt2 is not. The ablation of Akt1 promotes apoptosis and accelerates involution, whereas the ablation of Akt2 inhibits apoptosis and delays involution. Mammary gland differentiation during pregnancy depends on the phosphorylation of Stat5a, which is induced by prolactin, a hormone that generates signals transduced via Akt. Here we show that the ablation of Akt1, but not the ablation of Akt2 or Akt3 interferes with the phosphorylation of Stat5a during late pregnancy and lactation. We conclude that the three Akt isoforms have different roles in mammary gland differentiation during pregnancy and this may reflect differences in hormonal signaling.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA. imaroulakou@tuftsmedicalcenter.org
Ioanna G
IG
Maroulakou
William
W
Oemler
Stephen P
SP
Naber
Ina
I
Klebba
Charlotte
C
Kuperwasser
Philip N
PN
Tsichlis
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D004847:Epithelial Cells / Q000201:enzymology* / Q000637:transplantation; D005260:Female; D005838:Genotype; D007527:Isoenzymes; D007774:Lactation; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008892:Milk / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D007527:Isoenzymes; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt