The Role of PTEN in Progression of Ductal Carcinoma in situ
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: DCIS is an early lesion where the cancer cells are confined within the ducts of the breast. With the advent of better screening methods, the incidence of DCIS diagnosis is increasing. The most feared complication of DCIS is its tendency to invade out of the confines of the ducts and become invasive cancer. It is not known what genetic changes cause DCIS to become invasive. Thus, there is both a clinical and research need for better genetic markers that might predict, in each patient, whether DCIS is likely to become invasive cancer. This is a "quality of life" issue for the patient, because we want to spare women not at risk of invasive cancer the trauma of chemo- and radiation therapy. Our previous work, supported by a 2001 BCRP grant, identified that a gene called PTEN was a potential marker for DCIS progression. The PTEN protein works by modulating the activity of a potentially tumor-promoting signaling pathway inside of cancer cells, called PI3-kinase. Also, PTEN affects Akt-dependent cell survival signals, such that in the absence of active PTEN, tumor cells can avoid programmed cell death (apoptosis). 
 
 
 
 
 
 
 
 We have recently demonstrated that there are reduced amounts of PTEN protein in 40% of invasive human breast cancers as compared to DCIS lesions, which show reduction in only 10% of cases. These numbers are reasonable, since we expect only a fraction of DCIS patients to progress to invasive cancer. This is supported by those DCIS lesions that are associated with invasive cancer, which show a similar reduction in PTEN as the nearby invasive cancer. Based on this observations, we hypothesize that reduction of PTEN protein levels confer to the DCIS cells the capability of invading tissues and spreading. Using BCRP support we will, first, examine a large cohort of 500 DCIS cases for the presence of abnormalities in the PTEN gene structure and expression. Other cell proliferation and invasion proteins regulated by PTEN will also be analyzed like cyclin D1 and a laminin receptor, the integrin subunit 6. Secondly, we will obtain DCIS lesions that have recurred as invasive cancer and perform the same set of tests on the original DCIS in order to compare with the recurrent lesion. The above assays for abnormal PTEN protein levels and structural alterations will be performed on a tissue microarray (i.e., a microchip containing tissues from hundreds of different cases) that has been recently developed. We are adapting this approach to be more specific for DCIS lesions. We also hope to develop a novel assay to test for structural alteration of the PTEN gene, which if successful, will potentially impact not only the testing in breast cancers but also in many cancers from different organs like the ovary, skin, prostate, brain and thyroid.
 
 
 
 
 
 
 
 We predict that the presence of PTEN defects in DCIS cases will be both associated with invasive cancer and in recurrent DCIS lesions. We aim to develop the methodology to advance these genetic marker tests for routine clinical evaluation on this type of early breast cancer.