Transcriptome profiles of stem-like cells from primary breast cancers allow identification of ITGA7 as a predictive marker of chemotherapy response

• Published in: British journal of cancer 2021-09, Vol.125 (7), p.983-993
• Main Authors: Gwili, Noha, Jones, Stacey J., Amri, Waleed Al, Carr, Ian M., Harris, Sarah, Hogan, Brian V., Hughes, William E., Kim, Baek, Langlands, Fiona E., Millican-Slater, Rebecca A., Pramanik, Arindam, Thorne, James L., Verghese, Eldo T., Wells, Geoff, Hamza, Mervat, Younis, Layla, El Deeb, Nevine M. F., Hughes, Thomas A.
• Format: Article
• Language: English
• Subjects: 631/67/1059/99; 631/67/1347; 631/67/71; Antigens, CD - genetics; Antigens, CD - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer Research; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Down-Regulation; Drug Resistance; Drug Resistance, Neoplasm; Epidemiology; Female; Gene Expression Profiling - methods; Humans; Immunohistochemistry; Integrin alpha Chains - genetics; Integrin alpha Chains - metabolism; MCF-7 Cells; Molecular Medicine; Morphogenesis; Neoplastic Stem Cells - metabolism; Oncology; Sequence Analysis, RNA; siRNA; Stem cells; Survival Analysis; Transcriptomes
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01484-w

Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor ( n  = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq ( n  = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry ( n  = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.