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BC200 RNA: a novel molecular marker for DCIS and invasive breast cancer
Detection, Diagnosis and Prognosis
Early detection of breast cancer is essential to increase survival chances. Currently, there is no molecular marker available for the diagnosis of ductal carcinomas in situ (DCIS) or invasive carcinomas of the breast. Here we introduce BC200 RNA as a novel molecular indicator of invasiveness. BC200 RNA, a non-coding RNA that is normally expressed in neurons, has been reported to function as a translational modulator in postsynaptic microdomains. BC200 RNA is atypically expressed in various tumors, including squamous cell carcinomas of the lung, parotid carcinomas, and mammary carcinomas. Our previous results have shown that BC200 RNA is highly expressed in invasive carcinomas of the breast. The RNA is localized in tumor cells but it is not detectable in adjacent non-cancerous areas. In normal breast tissues and in benign tumors such as fibroadenomas, BC200 RNA expression does not differ significantly from background. In DCIS, BC200 expression levels are a direct reflection of tumor grade. We hypothesize that BC200 expression levels in DCIS lesions can serve as a prognostic indicator of future invasiveness. Therefore, in Specific Aim 1, we intend to establish the relationship between BC200 expression and tumor grade in DCIS. In Specific Aim 2, we will determine the discriminative power of BC200 RNA as indicator of malignancy in invasive carcinomas of the breast. We will use in situ hybridization to detect BC200 in breast tumor samples, and we will use image analysis routines to quantify signal intensity and distribution. In Specific Aim 3, we plan to establish a protocol to detect BC200 RNA quantitatively in small samples such as needle biopsies, using real-time RT-PCR methodologies. In summary, we plan to establish the utility of BC200 RNA as a prognostic molecular marker for DCIS and a diagnostic marker for invasive carcinomas of the breast.
Breast cancer prevention constitutes a major challenge in public health. Our research project aims at establishing BC200 RNA as a novel molecular tool in the diagnosis and prognosis of breast cancer. BC200 RNA is a small untranslated RNA that is expressed almost exclusively in the human nervous system. BC200 RNA is a translational repressor that is targeted to synaptodendritic domains of neurons where is has been suggested to modulate local protein synthesis. We have previously shown that BC200 expression is deregulated in mammary tumors but not in normal breast tissue. BC200 RNA is strongly expressed in high grade ductal carcinomas in situ (DCIS) and in invasive carcinomas. Conversely, the RNA is not expressed in benign tumors such as fibroadenomas, or in low grade DCIS. We propose that BC200 expression can be developed into a powerful molecular tool that will aid clinicians in the prognosis of DCIS and in the diagnosis of invasive carcinomas of the breast. In Specific Aim 1, we plan to validate BC200 expression in high grade vs. low grade DCIS, a discrimination that will eventually allow us to prognosticate if an early lesion will progress to an invasive tumor. In Specific Aim 2, we plan to investigate the reliability of BC200 RNA as tumor marker in invasive carcinomas of the breast, and to establish its utility in breast cancer diagnosis. In Specific Aim 3, we will quantify BC200 RNA in needle biopsies, using real-time PCR methodology. The ability to detect RNA in small samples will be critical for the clinical application of BC200 expression as a tumor marker. We believe that the proposed development of BC200 RNA as a molecular biomarker will be of great value for the diagnosis and prognosis of preinvasive and invasive lesions, and may consequently provide the basis for early treatment decisions.