Related Experiment Video

Updated: Feb 13, 2026

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
11:34

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers

Published on: December 5, 2017

13.1K

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes

Spencer S Watson1, Mark Dane1, Koei Chin1

  • 1Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

Cell Systems
|March 19, 2018
PubMed

Insights

Microenvironmental signals drive breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). Different HER2+ subtypes (HER2E and L-HER2+) exhibit distinct resistance mechanisms involving MET signaling and HER2-HER3 heterodimerization, respectively.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Extrinsic signals from the tumor microenvironment are increasingly recognized as key drivers of therapeutic resistance in cancer.
  • HER2-targeted tyrosine kinase inhibitors (TKIs) are crucial in treating HER2-positive breast cancer, but resistance remains a significant clinical challenge.
  • Understanding the specific microenvironmental factors and signaling pathways that mediate resistance is critical for developing more effective treatment strategies.

Purpose of the Study:

  • To investigate how specific microenvironmental signals influence resistance to HER2-targeted TKIs in different subtypes of HER2-positive breast cancer.
  • To identify distinct molecular mechanisms of TKI resistance in basal-like HER2-enriched (HER2E) and luminal-like HER2-positive (L-HER2+) breast cancer cells.
  • To explore potential therapeutic strategies for overcoming TKI resistance by targeting identified resistance pathways.

Main Methods:

  • Utilized microenvironment microarrays to test thousands of combinations of extracellular matrix and soluble proteins on TKI-treated HER2+ breast cancer cell lines.
  • Employed lapatinib and neratinib as model TKIs, assessing their efficacy in HER2E and L-HER2+ cells under various microenvironmental conditions.
  • Integrated bioinformatic pathway analysis and siRNA knockdown experiments to elucidate resistance mechanisms and validate findings in 3D cultures and murine xenografts.

Main Results:

  • Identified hepatocyte growth factor (HGF) as a driver of resistance in HER2E cells, which was reversible with MET inhibition (crizotinib).
  • Discovered neuregulin1-β1 (NRG1β) as a mediator of resistance in L-HER2+ cells, effectively reversed by targeting HER2-HER3 heterodimerization (pertuzumab).
  • Confirmed subtype-specific resistance mechanisms in advanced models, including 3D cultures and in vivo xenografts, highlighting the role of MET signaling in HER2E and HER2-HER3 in L-HER2+ cells.

Conclusions:

  • HER2-targeted TKI resistance in breast cancer is significantly influenced by subtype-specific microenvironmental signals.
  • MET signaling represents a critical resistance pathway in HER2E breast cancer, while HER2-HER3 heterodimerization is key in L-HER2+ subtypes.
  • These findings provide a basis for developing targeted combination therapies to overcome TKI resistance in distinct HER2-positive breast cancer subtypes.
Keywords:
HER2+ breast cancer subtypesHER3HGFNRG1βcrizotinibdrug resistancelapatinibmicroenvironmentneratinibpertuzumab

More Related Videos

Protocol for HER2 FISH Using a Non-cross-linking, Formalin-free Tissue Fixative to Combine Advantages of Cryo-preservation and Formalin Fixation10:21

Protocol for HER2 FISH Using a Non-cross-linking, Formalin-free Tissue Fixative to Combine Advantages of Cryo-preservation and Formalin Fixation

Published on: December 25, 2017

14.2K
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model09:29

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

19.0K

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.8K
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.1K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
7.2K
Mechanisms of Retrovirus-induced Cancers01:51

Mechanisms of Retrovirus-induced Cancers

Retroviruses are RNA viruses that have been shown to cause cancers in diverse species, including chickens, mice, cats, and monkeys. The RNA genomes of these viruses are first reverse-transcribed into single and then double-stranded DNA (dsDNA) copies. This dsDNA called proviral DNA then integrates into the host genome. Subsequently, the host cell transcribes the proviral DNA in concert with the chromosomal DNA. This leads to the production of viral RNA and proteins that assemble at the host...
7.0K
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
7.9K
Drug Absorption Mechanism: Carrier-Mediated Membrane Transport01:19

Drug Absorption Mechanism: Carrier-Mediated Membrane Transport

Certain large, lipid-insoluble drug molecules that resemble amino acids, peptides, or glucose, require specialized carrier proteins to facilitate their diffusion across cell membranes. This transport can occur through either facilitated diffusion, which does not require energy input, or active transport, which does require energy input.
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
6.3K