The estrogen receptor alpha (ERalpha) enhances or represses transcription by recruiting co-activator or co-repressor proteins to regulatory elements in the target genes. Cancers originating from estrogen-target tissues, such as breast and endometrium, are dependent on estrogen-ERalpha for growth. Anti-estrogens, such as tamoxifen, which block ERalpha activity by recruiting co-repressors or preventing co-activator recruitment, inhibit the growth of breast cancer cells. However, most of ERalpha-positive breast cancers eventually acquire estrogen-independent growth properties and become resistant to tamoxifen. We have discovered that the growth factor-regulated serine/threonine kinase AKT phosphorylates ERalpha in vitro and permits activation of ERalpha in the absence of estrogen. Ser167 in the negative regulatory region of the N-terminal activator function 1 (AF-1) domain of ERalpha is essential for phosphorylation and activation by AKT. PI3 kinase, the upstream activator of AKT, also increased AF-l activity, which was suppressed by the tumor suppressor gene PTEN. We also observed that AKT overexpression is sufficient to convert ERalpha-positive MCF-7 breast cancer cells from the tamoxifen-sensitive to the resistant phenotype. Tamoxifen-resistance correlated with estrogen-independent expression of the anti-apoptotic gene Bcl-2 and reduced apoptosis. From these results we hypothesize that: 1) AKT, by phosphorylating ERalpha, promotes recruitment of co-activator proteins to ERalpha in the absence of estrogen, which results in estrogen-independent expression of estrogen-regulated genes. 2) AKT, through ERalpha-dependent and ERalpha-independent mechanisms, protects cancer cells against tamoxifen-induced apoptosis. 3) Constitutive activation of AKT due to growth factor overexpression, gene amplification or loss of the tumor suppressor gene PTEN contributes to cancer development in estrogen-target tissues. The following studies will test these hypotheses: 1) we will determine how AKT modulates the co-activator and co-repressor:ERalpha interaction. 2) By using a dominant-negative ERalpha:co-repressor fusion gene, we will determine the relative importance of ERalpha-dependent and ERalpha-independent signaling events in AKT-mediated tamoxifen-resistance. 3) By inactivating PTEN, through a dominant-negative mutant or antisense RNA, we will determine whether loss of PTEN leads to increased ERalpha activity and tamoxifen-resistant growth of breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089153-04
Application #
6730553
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Forry, Suzanne L
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
4
Fiscal Year
2004
Total Cost
$234,675
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bhat-Nakshatri, Poornima; Song, Eun-Kyung; Collins, Nikail R et al. (2013) Interplay between estrogen receptor and AKT in estradiol-induced alternative splicing. BMC Med Genomics 6:21
Badve, Sunil; Collins, Nikail R; Bhat-Nakshatri, Poornima et al. (2010) Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: potential clinical implications. Am J Pathol 176:2139-49
Bhat-Nakshatri, Poornima; Wang, Guohua; Collins, Nikail R et al. (2009) Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res 37:4850-61
Badve, S; Nakshatri, H (2009) Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications. J Clin Pathol 62:6-12
Nakshatri, Harikrishna; Badve, Sunil (2009) FOXA1 in breast cancer. Expert Rev Mol Med 11:e8
Nakshatri, Harikrishna; Srour, Edward F; Badve, Sunil (2009) Breast cancer stem cells and intrinsic subtypes: controversies rage on. Curr Stem Cell Res Ther 4:50-60
Bhat-Nakshatri, Poornima; Wang, Guohua; Appaiah, Hitesh et al. (2008) AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer. Mol Cell Biol 28:7487-503
Prasad, Nagendra K; Tandon, Manish; Badve, Sunil et al. (2008) Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. Carcinogenesis 29:25-34
Tan, Bailin; Long, Xinghua; Nakshatri, Harikrishna et al. (2008) Striatin-3 gamma inhibits estrogen receptor activity by recruiting a protein phosphatase. J Mol Endocrinol 40:199-210
Mehta, S A; Christopherson, K W; Bhat-Nakshatri, P et al. (2007) Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion. Oncogene 26:3329-37

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