Abstract
Abstract
Background and Objectives: In 2021 breast cancer (BC) was the most common cancer affecting women and the second deadliest cancer in the U.S. Ductal Carcinoma In Situ (DCIS) is the earliest identifiable pre-invasive breast cancer lesion. Approximately 20-25% of diagnosed breast cancer cases are ductal carcinoma in situ (DCIS). Estimates show that 14 to 50% of DCIS cases progress to invasive breast cancer. We used a novel tissue-engineering system established in the Latimer laboratory to generate model systems representative of different molecular and histological subtypes of all stages of BC, including DCIS. Using a mass spectrometry (MS)-based relative quantitative methodology, we analyzed one novel DCIS cell line, the matching isogenic contralateral cell line and the non-tumor adjacent cell line, as well as two non-diseased breast reduction mammoplasty cell lines and the established stage IV BC cell lines MCF7 and MDA MB231. RNA sequencing analysis included additional cell lines from stages I, II and III. In order to limit the number of proteins for proteomic assessment, nuclear matrix proteins (NMPs) were targeted for analysis. NMPs have previously been linked with cancers of the prostate, colon, and breast. Maldi-TOF/TOF-MS analysis identified 270 NMPs with high confidence. Our objective was to identify NMPs with specifically altered expression in DCIS and later stages of BC compared to non-diseased breast and contralateral breast. Such markers may help to accurately identify invasive DCIS and improve early detection of BC. Results: We identified two nuclear matrix proteins that are significantly downregulated in DCIS and all other stages of BC in our collection. This downregulation was also apparent through mRNA expression analysis. These proteins are upregulated in non-diseased breast reduction tissue and contra-lateral DCIS derived from the same patient. We also identified four NMPs that were significantly upregulated in DCIS and all other BC stages compared to non-diseased breast reduction tissue and contralateral DCIS. Gene expression analyses showed that these four genes were upregulated with BC progression. Finally, we identified nine NMPS with significant differences in expression between DCIS and all stages of BC versus non-diseased breast reduction tissue and contralateral DCIS where gene expression did not follow the same trend as proteomic analysis. Conclusion: Our findings suggest that the changes that occur in the nuclear matrix of DCIS vs. normal breast epithelium could provide a basis for the development of prognostic biomarkers for DCIS and allow for targeted prevention of progression to invasive disease. This work was supported by grant W81XWH-0701-0660 from the DOD CDMRP BC program.
Citation Format: Ali Almutairy, Abdullah Alhamed, Stephen G. Grant, Miranda Sarachine Falso, Billy W. Day, Jean J. Latimer. Identification of cancer-specific alterations in expression of nuclear matrix proteins through proteomic and RNAsequencing analyses of ductal carcinoma in situ [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A033.