TY - JOUR
T1 - Akt-induced tamoxifen resistance is associated with altered FKHR regulation
AU - Silva, Jessica
AU - Cavazos, David A.
AU - Donzis, Elissa
AU - Friedrichs, William E.
AU - Marciniak, Robert
AU - DeGraffenried, Linda A.
N1 - Funding Information:
Keywords: Akt, tamoxifen, Forkhead, breast cancer, resistance These studies were funded in part by a grant to LAD by the Shelby Rae Tengg Foundation. Correspondence to: Linda A. deGraffenried Division of Medical Oncology UT Health Science Center at San Antonio 7703 Floyd Curl Dr. San Antonio, TX 78229 email: [email protected]
PY - 2007/10
Y1 - 2007/10
N2 - The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses, is associated with a poor pathophenotype in breast carcinoma, and is involved in hormone and chemotherapy resistance, including resistance to the antiestrogen, tamoxifen. Akt promotes cell survival by phosphorylating and inactivating proapoptotic proteins and increasing the transcription of survival genes. To explore the role that specific components of the Akt kinase pathway play in the cellular response to tamoxifen, we transfected MCF-7 cells with an expression plasmid for a constitutively active Akt. We found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models. Initial analysis of the molecular responses in the Akt/MCF-7 xenografts to tamoxifen suggests that high Akt activity alters apoptotic responses to tamoxifen. Control MCF-7 xenografts demonstrated activation of the proapoptotic forkhead (FKHR) transcription factor in response to tamoxifen treatment, while the xenografts expressing the constitutively active Akt transgene demonstrated no alterations in FKHR expression. In addition, TUNEL analysis demonstrated higher levels of apoptosis in the control xenografts in response to tamoxifen treatment compared to the Akt xenografts. Inhibition of Akt activity in vitro restored apoptotic responses to tamoxifen in the Akt/MCF-7 cells to those observed in the control cells. These data suggest that alteration of survival responses is an important mechanism by which Akt confers resistance to tamoxifen.
AB - The Akt kinase is a serine/threonine protein kinase that has been implicated in mediating a variety of biological responses, is associated with a poor pathophenotype in breast carcinoma, and is involved in hormone and chemotherapy resistance, including resistance to the antiestrogen, tamoxifen. Akt promotes cell survival by phosphorylating and inactivating proapoptotic proteins and increasing the transcription of survival genes. To explore the role that specific components of the Akt kinase pathway play in the cellular response to tamoxifen, we transfected MCF-7 cells with an expression plasmid for a constitutively active Akt. We found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models. Initial analysis of the molecular responses in the Akt/MCF-7 xenografts to tamoxifen suggests that high Akt activity alters apoptotic responses to tamoxifen. Control MCF-7 xenografts demonstrated activation of the proapoptotic forkhead (FKHR) transcription factor in response to tamoxifen treatment, while the xenografts expressing the constitutively active Akt transgene demonstrated no alterations in FKHR expression. In addition, TUNEL analysis demonstrated higher levels of apoptosis in the control xenografts in response to tamoxifen treatment compared to the Akt xenografts. Inhibition of Akt activity in vitro restored apoptotic responses to tamoxifen in the Akt/MCF-7 cells to those observed in the control cells. These data suggest that alteration of survival responses is an important mechanism by which Akt confers resistance to tamoxifen.
KW - Akt
KW - Breast cancer
KW - Forkhead
KW - Resistance
KW - Tamoxifen
UR - http://www.scopus.com/inward/record.url?scp=36248970239&partnerID=8YFLogxK
U2 - 10.1080/07357900701513538
DO - 10.1080/07357900701513538
M3 - Article
C2 - 17952739
AN - SCOPUS:36248970239
SN - 0735-7907
VL - 25
SP - 569
EP - 573
JO - Cancer Investigation
JF - Cancer Investigation
IS - 7
ER -