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- Title
The expression of activated Y-box binding protein-1 serine 102 mediates trastuzumab resistance in breast cancer cells by increasing CD44+ cells.
- Authors
Dhillon, Jaspreet; Astanehe, Arezoo; Fotovati, Abbas; Hu, Kaiji; Dunn, Sandra
- Abstract
The development of acquired resistance to trastuzumab remains a prevalent challenge in the treatment of patients whose tumors express HER2. We previously reported that HER2 over-expressing breast cancers are dependent on Y-box binding protein-1 (YB-1) for growth and survival. Since YB-1 is also linked to drug resistance in other types of cancer, we address its possible role in trastuzumab insensitivity. Employing an in vivo model of acquired resistance, we demonstrate that resistant cell lines have elevated levels of P-YB-1 S102 and its activating kinase P-RSK and these levels are sustained following trastuzumab treatment. Further, to demonstrate the importance of YB-1 in mediating drug resistance, the expression of the active mutant YB-1 S102D rendered the BT474 cell line insensitive to trastuzumab. Questioning the role of tumor initiating cells (TIC) and their ability to escape cancer therapies, we investigated YB-1's role in inducing the cancer stem cell marker CD44. Notably, the resistant cells expressed more CD44 mRNA and protein compared to BT474 cells, which correlated with increased mammosphere formation. Expression of YB-1 S102D in the BT474 cells increased CD44 protein levels, resulting in enhanced mammosphere formation. Further, exposing BT474 cells to trastuzumab selected for a resistant subpopulation enriched for CD44. Conversely, siRNA inhibition of CD44 restored trastuzumab sensitivity in the resistant cell lines. Our findings provide insight on a novel mechanism employed by tumor cells to acquire the ability to escape the effects of trastuzumab and suggest that targeting YB-1 may overcome resistance by eliminating the unresponsive TIC population, rendering the cancer sensitive to therapy.
- Subjects
CARRIER proteins; TRASTUZUMAB; CANCER patients; BREAST cancer; CANCER cells
- Publication
UBC Medical Journal, 2011, Vol 2, Issue 2, p53
- ISSN
1920-7425
- Publication type
Abstract