Related Experiment Video
Updated: Mar 17, 2026
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
ERBB2 Overexpression Establishes ERBB3-Dependent Hypersensitivity of Breast Cancer Cells to Withaferin A
Wenjun Liu1, Annalise R Barnette2, Samita Andreansky3,4
1Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida.
Abstract:
The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations. We found that ERBB2 overexpression does render cells hypersensitive to WA. Although ERBB2 downregulation is one aspect of WA treatment at high concentrations, it is not causal for the elevated sensitivity at lower dosages. Instead, WA targets the ability of ERBB3 to amplify ERBB2 signaling. ERBB3 receptor levels, constitutive phosphorylation of both ERBB3 and ERBB2, as well as signaling through AKT are eliminated by WA treatment. By targeting ERBB2/ERBB3 as a functional unit, it is also effective in cases in which ERBB2-directed inhibitors, such as lapatinib, alone show reduced potency. Hence, WA or derivatives thereof may present a low toxicity addition to ERBB2-targeting therapeutics, especially in cases in which ERBB3 involvement is driving resistance or reduced overall sensitivity. Mol Cancer Ther; 15(11); 2750-7. ©2016 AACR.
Insights
Withaferin A (WA) targets the ERBB3 receptor, enhancing ERBB2-targeted breast cancer therapies. This steroidal lactone overcomes resistance by inhibiting ERBB2/ERBB3 signaling, offering a potential low-toxicity treatment addition.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- ERBB3 deficiency synergizes with ERBB2, posing a risk factor for poor breast cancer outcomes.
- ERBB3 contributes to resistance against ERBB2-targeted therapies.
- Withaferin A (WA) exhibits anticancer properties and is effective against triple-negative breast cancer.
Purpose of the Study:
- To investigate the mechanism by which Withaferin A (WA) affects ERBB2/ERBB3 signaling in breast cancer.
- To determine if WA can overcome resistance to ERBB2-targeted therapies.
- To evaluate WA as a potential adjuvant therapy for breast cancer.
Main Methods:
- Cell-based assays to assess ERBB2/ERBB3 signaling pathways.
- Western blotting to analyze protein levels and phosphorylation.
- Treatment of breast cancer cells with WA and ERBB2 inhibitors (e.g., lapatinib).
Main Results:
- ERBB2-overexpressing cells exhibit hypersensitivity to WA.
- WA inhibits ERBB3-mediated amplification of ERBB2 signaling at lower concentrations.
- WA treatment reduces ERBB3 and ERBB2 levels and phosphorylation, and inhibits AKT signaling.
- WA demonstrates efficacy in models resistant to ERBB2-directed inhibitors.
Conclusions:
- Withaferin A targets the ERBB2/ERBB3 functional unit, not just ERBB2.
- WA can overcome resistance mechanisms in ERBB2-targeted breast cancer therapy.
- WA or its derivatives may serve as a low-toxicity addition to existing treatments, particularly when ERBB3 drives resistance.
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal