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Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development

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journal contribution
posted on 2023-01-06, 17:28 authored by Stephen MaddenStephen Madden, Mattia Cremona, Angela Farrelly, Weng Hei Low, Jean McBryanJean McBryan

To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.

Funding

Breast Cancer Ireland

The Physiological Society

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Madden SF, Cremona M, Farrelly AM, Low WH, McBryan J. Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development. Cancer Gene Ther. 2022.

Publication Date

20 October 2022

PubMed ID

36266450

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Molecular Medicine
  • Surgery

Research Area

  • Cancer
  • Endocrinology
  • Neurological and Psychiatric Disorders
  • Gynaecology, Obstetrics and Perinatal Health

Publisher

Nature Publishing Group

Version

  • Published Version (Version of Record)