Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: Potential clinical implications

Sunil Badve, Nikail R. Collins, Poornima Bhat-Nakshatri, Dmitry Turbin, Samuel Leung, Mangesh Thorat, Sandra E. Dunn, Tim R. Geistlinger, Jason S. Carroll, Myles Brown, Shikha Bose, Michael A. Teitell, Harikrishna Nakshatri

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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 ≈15 years follow-up and integrated these data with the expression of estrogen receptor (ER)α, progesterone receptor (PR), and FOXA1. Nuclear localization of pAKT (nuclear-pAKT) was associated with long-term survival (P = 0.004). Within the ERα+/PR+ subgroup, patients with nuclear-pAKT positivity had better survival than nuclear-pAKT-negative patients (P ≤ 0.05). The association of nuclear-pAKT with the ERα+/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 ERα-positive compared with ERα-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:ERα 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.

Original languageEnglish (US)
Pages (from-to)2139-2149
Number of pages11
JournalAmerican Journal of Pathology
Volume176
Issue number5
DOIs
StatePublished - May 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Badve, S., Collins, N. R., Bhat-Nakshatri, P., Turbin, D., Leung, S., Thorat, M., Dunn, S. E., Geistlinger, T. R., Carroll, J. S., Brown, M., Bose, S., Teitell, M. A., & Nakshatri, H. (2010). Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: Potential clinical implications. American Journal of Pathology, 176(5), 2139-2149. https://doi.org/10.2353/ajpath.2010.090477