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Cited by 54Estrogen and related hormone effectsAdvanced Breast Cancer TherapiesBreast Cancer Treatment Studies

Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo

Chen, Yi, Alvarez, Edwin A., Azzam, Diana, Wander, Seth A., Guggisberg, Natalia, Jordà, Mercè, Ju, Zhenlin, Hennessy, Bryan T., Slingerland, Joyce M.·2011·Breast Cancer Research and Treatment
DOI 10.1007/s10549-010-1024-7
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Abstract

Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.

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Cited by

Sorted by citations

Authors
Chen, Y., Alvarez, E. A., Azzam, D., Wander, S. A., Guggisberg, N., Jordà, M., Ju, Z., Hennessy, B. T., & Slingerland, J. M.
Affiliations
  • University of Miami (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
  • Chen, Yi
  • Slingerland, Joyce M.
ORCID
Venue
Breast Cancer Research and Treatment
Publisher
Springer Science and Business Media LLC
Published
2010-07-29
Volume
128
Issue
1
Pages
69-78
ISSN
  • 0167-6806 (ISSN-L)
  • 1573-7217
DOI
10.1007/s10549-010-1024-7
OpenAlex
W2068333274
Cited by
54
References
0
Citations by year
2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 10 · 2012: 9
FWCI
4.51
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Breast Cancer Research and Treatment (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
  • Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
Src kinase inhibition, saracatinib, fulvestrant, estrogen receptor-positive breast cancer, p27, antiestrogen resistance, combination therapy, mTOR signaling, mTORC1, drug resistance, cell cycle arrest, Ki-67
MeSH terms
Fulvestrant, Animals, Antineoplastic Agents, Breast Neoplasms, Drug Synergism, Estradiol, Female, Humans, Mice, Nude, Neoplasms, Hormone-Dependent, Quinazolines, Tamoxifen, G1 Phase, Drug Resistance, Neoplasm, src-Family Kinases, Ki-67 Antigen, Cyclin E, Xenograft Model Antitumor Assays, Cell Line, Tumor, Estrogen Receptor alpha, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 2, Mice, Benzodioxoles, TOR Serine-Threonine Kinases, ErbB Receptors

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