The PTEN/Akt Pathway in Ductal Carcinoma In Situ

Institution: Cedars-Sinai Medical Center
Investigator(s): Shikha Bose, M.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7KB-0131 Award: $99,604
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2001)
Ductal carcinoma in situ (DCIS) is a pre-cancerous lesion of the breast where the neoplastic cells are confined within the ducts of the breast. Unfortunately, 25-30% of DCIS cases will eventually progress to become invasive cancer. Clinicians need to be able to predict which DCIS patients will progress, so that these women can be treated more aggressively and monitored more carefully. Our hypothesis is that there are underlying genetic differences in DCIS that might be used to predict progression to invasive cancer.

We have preliminary information that loss of portion of chromosome 10 may play a role in the progress of DCIS to invasive cancer. PTEN is a recently identified gene, which is located in a part of chromosome 10 that is frequently lost in invasive breast cancer. The PTEN gene functions as a 'tumor suppressor', by serving as a 'brake' on certain key cellular growth and signaling pathways. PTEN regulates a number of genes and processes, which collectively we refer to as the PTEN/Akt pathway. As a result, if PTEN becomes lost or altered as a result of chromosome 10 changes, then this becomes permissive for invasive breast cancer. However, the underlying biology and genetic changes that links PTEN with breast cancer invasion and progression are not known. And, information needs to be developed to link chromosome 10 changes and PTEN with the clinical progression of DCIS.

We plan to create a tissue microarray (a chip containing hundreds of breast cancers) to study the relationship of PTEN and other genetic markers to determine their importance in breast cancer invasion and progression. We will thus be able to simultaneously test the the presence of altered genes in many women with precancer (DCIS) and compare and correlate them to women diagnosed with invasive breast cancer. We plan to use immunohistochemistry and fluorescence in situ hybridization (FISH) experiments to confirm the chromosome 10/PTEN link with the microarray data.

This project is a collaboration of clinical expertise and goals with newly emerging genetic analysis. We hope to develop information both on the underlying etiology of breast cancer as well as the key genetic elements relevant in the progression of the disease. This will provide the clinician with informative markers to make treatment decisions, and gives insight into which proteins and genes might best be investigated for new drug development.


Final Report (2002)
Note: Dr. Bose was funded in a new CBCRP grant in 2002 for an additional 18-months to continue her research.

Ductal carcinoma in situ (DCIS) is a pre-cancerous lesion of the breast where the neoplastic cells are confined within the ducts (not having escaped the basement membrane) of the breast. Unfortunately, 25-30% of DCIS cases will eventually progress to become invasive cancer. To be able to treat DCIS adequately clinicians need to be able to predict which DCIS patients will progress, so that these women can be treated more aggressively and monitored more carefully.

Our hypothesis is that there are underlying genetic differences in DCIS that might be used to predict progression to invasive cancer. We have preliminary information that loss of portion of chromosome 10 may play a role in the progress of DCIS to invasive cancer. PTEN is a recently identified gene, which is located in a part of chromosome 10 that is frequently lost in invasive breast cancer. The PTEN gene functions as a 'tumor suppressor', by serving as a 'brake' on certain key cellular growth and signaling pathways. PTEN regulates a number of genes and processes, which collectively we refer to as the PTEN/Akt signaling pathway. As a result, if PTEN becomes lost or altered as a result of chromosome 10 changes, then this becomes permissive for invasive breast cancer. However, the underlying biology and genetic changes that links PTEN with breast cancer invasion and progression are not known. And, information needs to be developed to link chromosome 10 changes and PTEN with the clinical progression of DCIS.

We have created a custom tissue microarray (a “gene chip”) containing 343 DCIS cases to study the relationship of PTEN and other genetic markers to determine their importance in breast cancer invasion and progression. We will thus be able to simultaneously test the presence of altered genes in many women with DCIS and compare and correlate them to women diagnosed with invasive breast cancer. We are in the process of using immunohistochemistry and fluorescence in situ hybridization (FISH) experiments to confirm the chromosome 10/PTEN link with the microarray data. We have standardized the procedure for performing the expression analysis of PTEN using four different antibodies, and for the analysis of phospho-Akt expression. In addition, we have made the probe for the genetic analysis of PTEN structure and are in the process of standardizing the procedure for our tissue array experiments.

This project is a collaboration of clinical expertise and goals with newly emerging “basic science” genetic analysis. We hope to develop information both on the underlying etiology of breast cancer as well as the key genetic elements relevant in the progression of the disease. This will provide the clinician with informative markers to make treatment decisions, and provide insight into which proteins and genes might best be investigated for new drug development.