Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: potential clinical implications.
Activated v-AKT murine thymoma viral oncogene homolog 1 (AKT)/protein kinase B (PKB) kinase (pAKT) is localized to the plasma membrane, cytoplasm, and/or nucleus in 50% of cancers. The clinical importance of pAKT localization and the mechanism(s) controlling this compartmentalization are unknown. In this study, we examined nuclear and cytoplasmic phospho-AKT (pAKT) expression by immunohistochemistry in a breast cancer tissue microarray (n = 377) with approximately 15 years follow-up and integrated these data with the expression of estrogen receptor (ER)alpha, progesterone receptor (PR), and FOXA1. Nuclear localization of pAKT (nuclear-pAKT) was associated with long-term survival (P = 0.004). Within the ERalpha+/PR+ subgroup, patients with nuclear-pAKT positivity had better survival than nuclear-pAKT-negative patients (P < or = 0.05). The association of nuclear-pAKT with the ERalpha+/PR+ subgroup was validated in an independent cohort (n = 145). TCL1 family proteins regulate nuclear transport and/or activation of AKT. TCL1B is overexpressed in ERalpha-positive compared with ERalpha-negative breast cancers and in lung metastasis-free breast cancers. Therefore, we examined the possible control of TCL1 family member(s) expression by the estrogen:ERalpha pathway. Estradiol increased TCL1B expression and increased nuclear-pAKT levels in breast cancer cells; short- interfering RNA against TCL1B reduced nuclear-pAKT. Overexpression of nuclear-targeted AKT1 in MCF-7 cells increased cell proliferation without compromising sensitivity to the anti-estrogen, tamoxifen. These results suggest that subcellular localization of activated AKT plays a significant role in determining its function in breast cancer, which in part is dependent on TCL1B expression.
Department of Pathology and Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. sbadve@iupui.edu
Sunil
S
Badve
Nikail R
NR
Collins
Poornima
P
Bhat-Nakshatri
Dmitry
D
Turbin
Samuel
S
Leung
Mangesh
M
Thorat
Sandra E
SE
Dunn
Tim R
TR
Geistlinger
Jason S
JS
Carroll
Myles
M
Brown
Shikha
S
Bose
Michael A
MA
Teitell
Harikrishna
H
Nakshatri
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D029681:Arabidopsis Proteins; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D029681:Arabidopsis Proteins; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C525633:TCL1 protein, Arabidopsis; C118783:TCL1B protein, human; D014157:Transcription Factors; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt