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.
Badve
Sunil
S
Department of Pathology and Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. sbadve@iupui.edu
Collins
Nikail R
NR
Bhat-Nakshatri
Poornima
P
Turbin
Dmitry
D
Leung
Samuel
S
Thorat
Mangesh
M
Dunn
Sandra E
SE
Geistlinger
Tim R
TR
Carroll
Jason S
JS
Brown
Myles
M
Bose
Shikha
S
Teitell
Michael A
MA
Nakshatri
Harikrishna
H
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