Characterization of Early Breast Cancer Driver IncRNAs
Abstract
This application addresses the following Overarching Challenges: Identify what drives breast cancer growth; determine how to stop it. Conquer the problems of overdiagnosis and overtreatment. Recent publications and comments in public forums argued that the routine use of screening mammography led to an overdiagnosis and overtreatment problem. The main argument by some epidemiologist and advisory groups is that even though since the 1980s we observed a dramatic increase in the detection of early-stage breast cancer, i.e., ductal carcinoma in situ (DCIS) and localized breast cancer, we did not observe a consequential proportional decrease in late-stage breast cancer in the following decades. It was argued that in 2008 breast cancer was overdiagnosed in more than 70,000 women in the United States, and this accounted for 31% of all breast cancers. Furthermore, it was suggested that the benefit of screening mammography is smaller than previously estimated and the harm of overdiagnosis is very significant not only because of the trauma and stigma attached to a cancer diagnosis, but more importantly because of the severity of the usual treatment. The problem is that these authors do not offer any hint of a solution, other than suggesting not screening for breast cancer, which is by no means a proper path in my humble opinion. It is beyond debate that the vast majority of invasive breast cancers (IBC) result from the progression of precursor DCIS lesions. Retrospective studies have concluded that women with biopsy-proven DCIS have over a 10-fold higher risk for developing IBC than women without DCIS history. If left untreated, it has been estimated that at least one-third of all DCIS are likely to progress to IBC during the life of the patient. Thus, once DCIS is detected, it cannot be disregarded as an inconsequential finding. By definition, every DCIS is a time bomb. The issue is discerning which of these time bombs are activated and which are not. Why is it that approximately only a third of DCIS lesions appear to have the potential to evolve to full-blown invasive breast carcinoma during the lifetime of a patient while two-thirds do not? Unfortunately, the answer is: we do not know. We do not understand the molecular triggers that propel DCIS lesions to progress to IBC. An additional problem is that the majority of DCIS patients are treated the same way with local excision (sometimes even mastectomy) plus radiation therapy or hormonal therapy. However, approximately 70%-75% of these patients would not have tumor recurrences even if they had not received any adjuvant therapy, which constitutes an additional overtreatment conundrum. In preliminary studies now submitted for publication, we report a first comprehensive molecular profiling study of aggressive DCIS lesions. One of the major findings was detecting the increase expression of almost 200 long-non-coding RNAs (lncRNAs). These elements (lncRNAs) are not genes that typically encode proteins. Now we know there are thousands of these elements scattered throughout the human genome, and we are just starting to understand what functions they play. We do know, however, that some of them behave like oncogenes; they can be used as biomarkers of tumor progression and as potential therapeutic targets as well. Objective, Hypothesis, and Impact: We propose to identify and characterize novel lncRNAs associated with, and responsible for, the progression of DCIS to IBC. Our hypothesis is that specific lncRNAs we identified as abnormally expressed in DCIS operate as either promoters or suppressors of breast tumor progression. Identifying key molecular targets involved in the transition from an in situ breast precancerous condition into an invasive tumor will provide a better understanding of the mechanisms that govern early breast tumor progression. The ultimate goal is to identify novel targets for the development of improved methods of detection and the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610027
Entities
People
- Claudio Aldaz
Organizations
- United States Army
- University of Texas at Austin