Related Experiment Video

Updated: Feb 12, 2026

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers
06:02

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers

Published on: February 20, 2017

8.0K

ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to

Angel L Guerrero-Zotano1, Thomas P Stricker2, Luigi Formisano1

  • 1Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 28, 2018
PubMed

Insights

This study identified an E2F4 target gene signature linked to endocrine resistance in ER+ breast cancer. CDK4/6 inhibitors suppressed this signature, suggesting their potential benefit for patients resistant to estrogen deprivation therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Endocrine therapy resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer treatment.
  • Prolonged neoadjuvant endocrine therapy aims to improve surgical outcomes but can lead to resistance.
  • Identifying biomarkers for endocrine resistance is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To identify biomarkers associated with resistance to prolonged neoadjuvant letrozole in ER+ breast cancer.
  • To investigate the role of E2F4 target gene activation in endocrine resistance.
  • To evaluate the efficacy of CDK4/6 inhibitors in overcoming endocrine resistance.

Main Methods:

  • Targeted DNA and RNA sequencing of 68 ER+ breast tumors treated with neoadjuvant letrozole.
  • Integration of gene expression data with transcription-binding data to identify regulatory networks.
  • Analysis of gene expression changes in response to CDK4/6 inhibitors (palbociclib), fulvestrant, and paclitaxel in cell lines and patient tumors.
  • Correlation of E2F4 activation signature with clinical outcomes in independent breast cancer trials.

Main Results:

  • A gene expression signature of E2F4 target activation was identified in tumors resistant to letrozole.
  • CDK4/6 inhibitor palbociclib significantly downregulated E2F4 target genes in both preclinical models and patient tumors.
  • E2F4 activation signature correlated with resistance to aromatase inhibitors and increased relapse risk in ER+ breast cancer patients.
  • Fulvestrant and paclitaxel showed less efficacy in suppressing the E2F4 target gene signature compared to palbociclib.

Conclusions:

  • E2F4 target gene activation represents a key mechanism in endocrine resistance to prolonged neoadjuvant letrozole.
  • CDK4/6 inhibition effectively suppresses the E2F4 activation signature, offering a potential therapeutic strategy.
  • Adjuvant CDK4/6 inhibitors may benefit ER+ breast cancer patients who exhibit resistance to neoadjuvant estrogen deprivation therapy.

More Related Videos

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
Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma09:11

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

Published on: May 24, 2024

1.2K

Related Concept Videos

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
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
Transcription01:10

Transcription

Overview
Transcription is the process of synthesizing RNA from a DNA sequence by RNA polymerase. It is the first step in producing a protein from a gene sequence. Additionally, many other proteins and regulatory sequences are involved in the proper synthesis of messenger RNA (mRNA). Regulation of transcription is responsible for the differentiation of all the different types of cells and often for the proper cellular response to environmental signals.
Transcription Can Produce Different Kinds...
157.1K
Transcription Factors02:16

Transcription Factors

Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
82.9K
Eukaryotic Transcription Activators02:42

Eukaryotic Transcription Activators

Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
12.9K
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.8K