PAK1 hyperactivation is sufficient for mammary gland tumor formation.
Emerging data suggest that p21-activated kinase 1 (Pak1), a downstream signaling molecule of the small GTPases, growth factors, and lipid signaling, is upregulated or hyperactivated in human breast cancer. Until now, however, no direct causative role had been found for Pak1 in mammary tumor formation. We therefore sought to identify the role that Pak1 plays in mammary gland tumorigenesis. Our results showed that in a transgenic mouse model, overexpression of catalytically active Pak1 leads to the development of malignant mammary tumors and to a variety of other breast lesions, including focal solid nodules, ductal hyperplasia, and mini-intraductal neoplasm and adenoma. We also found that Pak1 hyperactivation increases the stimulation of downstream proliferative signaling effectors MEK1/2 and p38-MAPK in mammary tumor epithelial cells. Moreover, in our study, we detected expression of estrogen receptor-alpha expression and progesterone receptor expression during early stages of the lesions, but their expression was lost during the cells' transition to malignant invasive tumors. Finally, we found that consistent with a role in breast tumor progression, Pak1 expression and its nuclear accumulation was increased progressively during the transition from ductal hyperplasia to ductal carcinoma in situ to adenocarcinoma in widely used multistep polyoma-middle T-antigen transgenic mice. Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors.
Wang
R-A
RA
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA.
Zhang
H
H
Balasenthil
S
S
Medina
D
D
Kumar
R
R
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015854:Up-Regulation; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse