Download Ph.D. Student: Karina Hedelund Gravgaard Enrolment: 1 July 2010

Ph.D. Student: Karina Hedelund Gravgaard
Enrolment:
1 July 2010
Project Title: MicroRNAs associated with tumor progression and endocrine resistance in breast
cancer tumors
Supervisors:
Professor Henrik J. Ditzel, dr.med, PhD,Consultant Anne-Vibeke Lænkholm
Consultant Ann Knoop
Institute:
Institute of Molecular Medicine
Research Unit: Cancer and Inflammation Research
Abstract:
Introduction: Approximately 80% of diagnosed breast cancers are estrogen receptor-positive (ER+)
and receive adjuvant endocrine treatment with either Tamoxifen or aromatase inhibitors (AI),
thereby reducing the overall risk of development of metastases. However, approximately 30% of
the ER+ breast cancer patients still develop metastases indicating that detection of ER by itself is
not sufficient to predict benefit of endocrine therapy. Therefore the identification of additional
predictive biomarkers is crucial for optimization of the efficacy of current treatments of ER+ breast
cancers. The purpose of this translational project is to identify and validate microRNA (miRNA)
markers that potentially can be used to assist clinicians in choice of optimal treatment of breast
cancer. These studies will focus on identification of miRNAs 1) specifically associated with
endocrine treatment response in patients with ER+ breast cancer and 2) predictive of progression of
DCIS. The miRNAs will be identified by comparing the global miRNA expression profile of a large
number of tumor samples from patients with vs. without recurrence following long-term endocrine
treatment and by comparing the global miRNA expression of tissue from DCIS cases that resulted
in local recurrence with those that did not. An additional purpose of the project is to study miRNA
expression alterations associated with metastasis as we have recently identified miRNAs that may
be central in the metastatic process. Our study thus addresses three clinical very important areas and
should in long term bring insight to the biology of miRNAs and improve the treatment of breast
cancer patients.
Methods: Global miRNA analysis: microarray or a qPCR platform. Validation: miRNA qRT-PCR.
Validated miRNAs will be investigated using endocrine resistant cell lines where the miRNAs will
be either knocked down or over expressed in the cell lines for functional studies. Protein expression
of potential miRNA targets in breast cancers tissue and corresponding metastases will be
investigated using immunohistochemical (IHC) analysis and the cellular localization of the
differentially expressed miRNAs will be investigated using in situ hybridization.
Current status: The IHC analysis has been performed and in situ hybridization of two of the
identified miRNAs is being performed at the moment.
Keywords: Oncology and Haematology