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Mutations

Mutations

Mutations

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...

Cancers Originate from Somatic Mutations in a Single Cell

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...

Viral Mutations

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...

Mutation, Gene Flow, and Genetic Drift

Mutation, Gene Flow, and Genetic Drift

In a population that is not at Hardy-Weinberg equilibrium, the frequency of alleles changes over time. Therefore, any deviations from the five conditions of Hardy-Weinberg equilibrium can alter the genetic variation of a given population. Conditions that change the genetic variability of a population include mutations, natural selection, non-random mating, gene flow, and genetic drift (small population size).

Point and Frameshift Mutations

Point and Frameshift Mutations

Point mutations are genetic alterations involving the change of a single nucleotide base pair in DNA. Depending on how the alteration affects protein synthesis, they can lead to various consequences.Point mutations fall into the following types:Silent mutations occur when a nucleotide change does not alter the amino acid sequence due to the redundancy of the genetic code. For instance, changing ACC to ACA still encodes threonine, leaving the protein function unaffected. This occurs because...

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Related Experiment Video

Updated: Feb 8, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

Activating HER3 mutations in breast cancer.

Rosalin Mishra¹, Samar Alanazi¹, Long Yuan¹

¹James L. Winkle College of Pharmacy, University of Ohio, Cincinnati, Ohio, USA.

|July 3, 2018

Summary

HER3 mutations can activate breast cancer cell proliferation independently of HER2. The HER3^T355I mutant drives growth in ER+ cells via HER4/HER1 pathways, impacting treatment responses.

Keywords:

ER HER2 HER3 Targeted Therapy mutation

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Area of Science:

Oncology
Molecular Biology
Cancer Genetics

Background:

Recent research implicates HER3 in estrogen receptor (ER) and HER2-driven breast cancers.
Understanding the impact of HER3 mutations is crucial for targeted therapies.

Purpose of the Study:

To investigate the functional role of patient-derived HER3 mutations in ER-positive (ER+) and HER2-positive (HER2+) breast cancer cells.
To assess the effect of these mutations on cancer cell proliferation and response to inhibitors.

Main Methods:

Ectopic expression of HER3 mutants in ER+ (T47D, MCF-7) and HER2-overexpressing (MCF10AHER2) breast cancer cell lines.
Immunoblotting and receptor tyrosine kinase arrays to analyze signaling pathways.
Assessment of cell proliferation, heterodimerization, and response to lapatinib.
HER3 knockdown in ovarian and colorectal cancer cell lines with endogenous HER3 mutations.

Main Results:

The HER3^T355I mutant demonstrated activating properties, increasing cell proliferation in ER+ cells lacking HER2 overexpression.
HER3^T355I expression led to increased phosphorylation of HER4 and HER1, activating ERK1/2 and cyclin D1 pathways.
Estrogen receptor alpha (ERα) expression was upregulated, with observed crosstalk between ERα and HER3.
Several HER3 mutants (F94L, G284R, D297Y, T355I, E1261A) exhibited gain-of-function phenotypes in HER2-overexpressing cells, conferring resistance to lapatinib and increasing HER2-HER3 heterodimerization.
Knockdown of HER3 abrogated proliferation in ovarian and colorectal cancers with endogenous HER3 mutations.

Conclusions:

HER3 mutations can be activating independently of HER2 overexpression, driving proliferation in ER+ breast cancer.
The HER3^T355I mutant's mechanism involves HER4/HER1-dependent pathways and ERα crosstalk.
Mutant HER3 confers resistance to lapatinib and promotes HER2-HER3 heterodimerization.
HER3 mutations play a significant role in various cancer types, including ovarian and colorectal cancers.