Related Experiment Video

Updated: Mar 3, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

7.7K

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Babak Nami1, Zhixiang Wang2

  • 1Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 8-35 Medical Sciences Building, 114 St., Edmonton, AB T6G 2H7, Canada. namimoll@ualberta.ca.

Cancers
|April 27, 2017
PubMed

Insights

HER2+ breast cancer resistance to trastuzumab may stem from a feedback loop. HER2 signaling promotes cancer stem cell traits and epithelial-mesenchymal transition, leading to HER2 shedding and treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • HER2 receptor tyrosine kinase is overexpressed in 20% of breast cancers (BCs), serving as a poor prognosis factor and therapeutic target.
  • Trastuzumab targets HER2 in HER2+ BC, but de novo resistance develops in ~60% of patients, often due to HER2 extracellular domain shedding.
  • HER2 shedding, mediated by metalloproteinases, yields p95HER2, a marker for trastuzumab resistance and linked to mesenchymal-like cancer stem cells.

Purpose of the Study:

  • To review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives trastuzumab resistance in breast cancer.
  • To explore the role of epithelial-to-mesenchymal transition (EMT) and cancer stem cells in HER2 shedding and resistance.
  • To elucidate the interaction between HER2 and oncogenic/stemness pathways.

Main Methods:

  • Literature review of studies on HER2, trastuzumab resistance, metalloproteinases, EMT, and cancer stem cells.
  • Analysis of signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT, and Hedgehog in relation to HER2 and stemness.
  • Hypothesizing a negative feedback loop mechanism.

Main Results:

  • HER2 overexpression promotes EMT and cancer stem cell properties.
  • Increased metalloproteinase activity during EMT leads to HER2 cleavage and shedding, reducing the extracellular domain.
  • This shedding downregulates HER2 signaling and contributes to trastuzumab resistance, while tumors may remain sensitive to lapatinib.

Conclusions:

  • A negative feedback loop between HER2 and stemness signaling, involving EMT and metalloproteinase-mediated shedding, is proposed as a key driver of trastuzumab resistance in HER2+ breast cancer.
  • Understanding this loop may reveal new therapeutic strategies targeting resistance mechanisms.
  • p95HER2 accumulation and metalloproteinase upregulation are critical events in the development of resistance.
Keywords:
EMTHER2/ERBB2breast cancercancer stem cellmetalloproteinasep95HER2signalingstemnesstrastuzumab

More Related Videos

Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples07:03

Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples

Published on: October 2, 2020

5.2K
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery13:19

Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery

Published on: April 26, 2024

4.0K

Related Concept Videos

Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
6.2K
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
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
9.0K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
8.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K
Cell Signaling Feedback Loops01:07

Cell Signaling Feedback Loops

Positive and negative feedback loops are crucial for regulating biological signaling systems. These feedback loops are processes that connect output signals to their inputs.
Negative feedback loops
Most signaling systems have negative feedback loops that can perform different functions such as output limiter, and adaptation.
Output limiter
Upon receiving an input signal, the cellular response rapidly increases until a threshold is reached. Beyond this threshold, a negative feedback loop...
7.5K