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Title

The Role of the ETS Transcription Factor, ESE-1, in Cancer

Status

Open

Project Description

        The main focus of my laboratory is to determine the role of Ets transcription factors in epithelial cell development and tumorigenesis, with a focus on pituitary, mammary and now ovarian model systems. In our pituitary project, we study how the combinatorial action of Ets factors, Ets-1 and GABP, act in concert with the POU-homeodomain transcription factor, Pit-1, to regulate the lactotrope-specific basal and Ras-regulated expression of the prolactin gene. Utilizing biochemical, structural, molecular and transgenic approaches, we have discovered that Ets factors play a critical role in specifying lactotrope cell identity in pituitary ontogeny.  More recently, we have initiated studies to elucidate the molecular mechanisms by which lactotrope adenomas arise and why they rarely progress to frank carcinoma, focusing on the role of adult pituitary progenitor/stem cells in facultative lactotrope expansion during pregnancy and in tumorigenesis. With regards to our breast cancer project, we study the role of the epithelial-specific Ets transcription factor, ESE-1, in human mammary epithelial cell tumorigenesis. ESE-1 is over-expressed in many breast cancers and, thus, it is particularly relevant in human disease. We have shown that ESE-1 confers a transformed phenotype to immortalized, but nontransformed MCF-12A human mammary epithelial cells via a novel cytoplasmic mechanism, such that the exclusive cytoplasmic targeting of a unique, 40-AA serine- and aspartic rich (SAR) subdomain is both necessary and sufficient for the transformation response. In contrast, ESE-1 is expressed in the nucleus in established breast cancer cell lines, and knockdown of ESE-1 reverses the transformed state. In sum, our studies reveal that ESE-1 acts via a cytoplasmic mechanism to initiate transformation, but once mammary cells are fully transformed, then nuclear ESE-1 is required to maintain the malignant phenotype. We have developed monoclonal antibodies specifically targeting ESE-1 and we are working with collaborators using these mAbs in IHC studies to determine the correlation between ESE-1 expression and breast cancer subtype and outcomes. We are making a significant commitment to deep DNA sequencing, xenograft tumor and transgenic approaches to decipher the role of specific POU-homeodomain and Ets transcription factors in mediating the ontogeny, maintenance and tumorigenesis of pituitary, mammary and ovarian epithelial cells.

Mentor Name

Gutierrez-Hartmann, Arthur

Mentor Location

Research Tower I South, Rm 7108

Mentor Contact Number

303-724-4600

Mentor Contact Email

a.gutierrez-hartmann@ucdenver.edu

Specialty

Enter Choice #1

Preceptor Name

 

Student

 

Department

Medicine

Funding Department/Program

Medicine

Area of Study

Hematology and Oncology

Populations

Adults; Women

Method(s)

Cell Biology, Molecular Biology, and Genetics

Disease or Symptom

Cancer

Faculty/Lab Website

http://www.ucdenver.edu/cancerbiology

Display on public listings?

Yes

Attachments

Created at 6/17/2011 8:54 AM by Vetter, Stephanie
Last modified at 7/9/2013 1:50 PM by Watts, Katie