Guest, S. K., Ribas, R., Pancholi, S., Nikitorowicz-Buniak, J., Simigdala, N., Dowsett, M., Johnston, S. R., Martin, L. A. (2016) Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation. PLOS ONE, 11 (6). ISSN 1932-6203

Preview

Text 15209.pdf Download (3MB) | Preview

Abstract

Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pansrc inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib +/- endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection for clinical trials testing dasatinib utility in ER+ breast cancer.

Item Type:	Article
Authors (ICR Faculty only):	Dowsett, Mitch and Martin, Lesley-Ann
All Authors:	Guest, S. K., Ribas, R., Pancholi, S., Nikitorowicz-Buniak, J., Simigdala, N., Dowsett, M., Johnston, S. R., Martin, L. A.
Additional Information:	ISI Document Delivery No.: DO8JO Times Cited: 0 Cited Reference Count: 42 Guest, Stephanie K. Ribas, Ricardo Pancholi, Sunil Nikitorowicz-Buniak, Joanna Simigdala, Nikiana Dowsett, Mitch Johnston, Stephen R. Martin, Lesley-Ann Breast Cancer Now; NHS funding to the Royal Marsden Hospital's NIHR Biomedical Research Centre The authors acknowledge Breast Cancer Now and NHS funding to the Royal Marsden Hospital's NIHR Biomedical Research Centre for funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 0 PUBLIC LIBRARY SCIENCE SAN FRANCISCO PLOS ONE
Uncontrolled Keywords:	ER-ALPHA PHOSPHORYLATION TAMOXIFEN-RESISTANT ANTITUMOR-ACTIVITY MOLECULAR MARKERS DASATINIB THERAPY PATIENT SELECTION KINASE INHIBITOR GENE-EXPRESSION MCF-7 CELLS PATHWAYS
Research teams:	ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Barry Jenkins
Date Deposited:	27 Jul 2016 14:44
Last Modified:	27 Jul 2016 14:51
URI:	http://publications.icr.ac.uk/id/eprint/15209

Actions (login required)

View Item