Breast cancer is the most frequently diagnosed cancer in U.S. women, excluding nonmelanoma skin cancers. While mammography use has enhanced breast cancer survival, better methods are needed for screening for early detection, especially in younger women. Analysis of blood for circulating tumor markers may be useful in breast cancer screening. MicroRNAs (miR) are small (22-25 nucleotides in length) noncoding RNAs that can effectively reduce the translation of target messenger RNAs by binding to their 3'untranslated region (UTR). miRs have been proposed to contribute to oncogenesis because they can function either as tumor suppressors or oncogenes. Abnormal levels of expression for mature and/or precursor miR sequences compared with the corresponding normal tissues have been observed. Other studies have demonstrated that miRs can be found in the blood and are highly stable. These results have lead to the hypothesis that plasma levels of miRs might be useful for early diagnosis of cancer. This proposal seeks to obtain pilot funding to identify candidate biomarker miRs overexpressed in plasma of breast cancer cases compared to controls and to establish the laboratory assays for their quantitation in plasma. Breast tumor, adjacent tissues, and the corresponding bloods are available from consenting, newly-diagnosed breast cancer cases seen at Columbia University Medical Center. These resources will enable us to identify plasma miRs as promising novel biomarkers for early detection of breast cancer. There are two specific aims.
Aim 1 will compare whole genome miR expression profiles in 20 plasma samples from breast cancer cases and 20 age- and ethnicity-matched controls. The top 5-10 miRs overexpressed in cases will then be assayed using a real time quantitative PCR (RT-qPCR) assay to confirm the array data and then paraffin section breast tumor/paired adjacent tissues will be analyzed to determine if they are also overexpressed in tumor compared with adjacent tissues.
In Aim 2 the RT-qPCRs will be used to confirm case/control plasma differences using an independent set of 100 cases and matched controls. This pilot study will provide the resources to select breast cancer-specific miRs, establish the laboratory assays for quantitation of miRs in plasma, and demonstrate that we can detect breast cancer at the time of diagnosis. Our long term goal is to use bloods collected from participants in the Breast Cancer Family Registry, an international registry of families at high risk for breast cancer in which bloods are available prior to diagnosis. The development of screening methods for the early detection of breast cancer in high risk populations will lead to better treatment and survival.
This pilot study will identify miRs upregulated in plasma of breast cancer cases compared to controls that can potentially be used to screen for early diagnosis of breast cancer. The development of real time assays for their measurement in plasma and pilot data on breast cancer cases and controls will be essential for future funding of a large prospective study.
|D'Amico, Emanuele; Factor-Litvak, Pam; Santella, Regina M et al. (2013) Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 65:509-27|