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Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers - role of estrogen receptor and HER2 reactivation

Overview of attention for article published in Breast Cancer Research, November 2011
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (91st percentile)
  • High Attention Score compared to outputs of the same age and source (92nd percentile)

Mentioned by

patent
10 patents

Citations

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217 Dimensions

Readers on

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220 Mendeley
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Title
Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers - role of estrogen receptor and HER2 reactivation
Published in
Breast Cancer Research, November 2011
DOI 10.1186/bcr3067
Pubmed ID
Authors

Yen-Chao Wang, Gladys Morrison, Ryan Gillihan, Jun Guo, Robin M Ward, Xiaoyong Fu, Maria F Botero, Nuala A Healy, Susan G Hilsenbeck, Gail Lewis Phillips, Gary C Chamness, Mothaffar F Rimawi, C Kent Osborne, Rachel Schiff

Abstract

The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs. Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts. ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L- and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts. Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients.

Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 220 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 2 <1%
Norway 1 <1%
Turkey 1 <1%
Russia 1 <1%
Argentina 1 <1%
Unknown 214 97%

Demographic breakdown

Readers by professional status Count As %
Researcher 44 20%
Student > Ph. D. Student 43 20%
Student > Master 30 14%
Student > Bachelor 23 10%
Student > Doctoral Student 12 5%
Other 29 13%
Unknown 39 18%
Readers by discipline Count As %
Agricultural and Biological Sciences 53 24%
Biochemistry, Genetics and Molecular Biology 42 19%
Medicine and Dentistry 40 18%
Chemistry 10 5%
Pharmacology, Toxicology and Pharmaceutical Science 9 4%
Other 20 9%
Unknown 46 21%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 12. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 July 2022.
All research outputs
#2,863,523
of 25,371,288 outputs
Outputs from Breast Cancer Research
#296
of 2,052 outputs
Outputs of similar age
#20,675
of 246,482 outputs
Outputs of similar age from Breast Cancer Research
#4
of 54 outputs
Altmetric has tracked 25,371,288 research outputs across all sources so far. Compared to these this one has done well and is in the 88th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,052 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.2. This one has done well, scoring higher than 85% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 246,482 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 91% of its contemporaries.
We're also able to compare this research output to 54 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 92% of its contemporaries.