Project: Research project

Project Details


DESCRIPTION (provided by applicant): 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.
Effective start/end date5/1/014/30/07


  • National Institutes of Health: $234,675.00
  • National Institutes of Health: $234,675.00
  • National Institutes of Health: $234,675.00
  • National Institutes of Health: $234,675.00
  • National Institutes of Health: $234,675.00


  • Medicine(all)


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