The impact of epigenetic features on breast cancer treatment and outcomes

In a recent review published in the Cancers Journal, a group of authors analyzed the impact of epigenetic features on breast cancer treatment and outcomes, emphasizing chromatin changes and the potential of targeting epigenetic enzymes for improved patient results.

Study: Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response. Image Credit: Gorodenkoff/Shutterstock.comStudy: Emerging Role of Epigenetic Modifiers in Breast Cancer Pathogenesis and Therapeutic Response. Image Credit: Gorodenkoff/Shutterstock.com

Background

Breast cancer heterogeneity results in four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC). Their classification depends on the expression of progesterone receptor (PR), estrogen receptor (ER), and HER2.

Luminal A is the most prevalent, constituting 60-70% of cases, characterized by ER and/or PR positivity, HER2-negativity, and low proliferation. They typically respond well to hormone therapies. Luminal B, more aggressive and constituting about 10% of cases, is ER-positive and may be PR-positive/negative.

Around 30% of luminal B tumors also express HER2. HER2-positive tumors, 10-15% of cases, show improved prognosis due to HER2-targeted treatments. TNBCs, accounting for 10-20% of diagnoses, are aggressive and originate from basal cells, lacking ER, PR, and HER2 expression.

Histone-Modifying complexes

In breast cancers, the histone 3 lysine 4 (H3K4) methyltransferase-specific complex of proteins associated with set1 (COMPASS) complexes often experience dysregulation. These complexes, driven by six set1/ mixed lineage leukemia (MLL) methyltransferases, oversee the methylation levels of H3K4, generally promoting transcriptional activation.

A particular challenge arises in HR-positive, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutant breast cancers where clinical PI3K inhibition leads to amplified ER signaling.

Research indicates that the AKT kinase modifies MLL4/KMT2D methyltransferase's activity. Enhanced MLL4 activity, caused by PI3K inhibition, advances an open chromatin state, further supporting the binding of specific transcription factors to the genome.

Meanwhile, improper H3K4 methylation can endanger cell regulation and promote unfavorable outcomes in advanced breast cancers. Addressing these irregularities could help curtail the growth of HR-positive breast tumors.

Concurrently, the SWItch-mating type/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complexes, crucial for gene expression regulation, deoxyribonucleic acid (DNA) damage response, and cell differentiation, have shown to be dysregulated in advanced breast cancers.

Variations in these complexes, especially in the brahma-related gene 1 (BRG1)/BRM-associated factor (BAF) complex protein AT-rich interaction domain 1A (ARID1A), are observed more in metastatic breast cancers.

Such alterations, especially the loss of ARID1A, weaken the cancer cell's response to certain treatments. ARID1A has a pivotal role in luminal breast lineage maintenance.

Its loss can shift the cellular profile, making them independent of ER. The dynamic interplay of these complexes suggests potential treatment strategies, with some implying the benefits of targeting BRG1 or inhibiting PI3K in certain patient cohorts.

Histone acetyltransferases

Histone acetylation, controlled by histone acetyltransferases (HATs) and countered by histone deacetylases (HDACs), is a dynamic modification influencing gene expression. These HAT enzymes add acetyl groups to histone tails, loosening the DNA-histone interaction and enabling transcription.

Within breast cancer, aberrant histone acetylation plays a role in progression and therapeutic outcomes. A study involving 880 breast carcinomas found variations in H4K16 acetylation levels linked to disease progression and survival.

Moreover, histone acetylation patterns can distinguish between different breast cancer types. For example, H3K9ac appears common in TNBC and HER2-positive tumors, while H3K27me3 is typical in luminal subtypes.

Some HATs directly affect tumor characteristics, with studies suggesting their potential as a therapeutic target in breast cancers. They also act in epithelial-to-mesenchymal transition (EMT) and DNA damage response.

For instance, in TNBC, the HAT P300/CBP-Associated Factor (PCAF) influences replication fork degradation. Preclinical research delves into HAT inhibitors, yet clinical applications remain largely unexplored. In contrast, HDAC inhibition has seen more extensive research and clinical testing.

HDACs in breast cancer

HDACs play a pivotal role in modulating the structure and function of chromatin by deacetylating lysine residues, counteracting the effects of HAT. In humans, 18 known types of HDACs are categorized into four classes based on their similarities to yeast proteins.

Classes I, II, and IV operate through zinc-dependent catalysis, while class III relies on nicotinamide adenine dinucleotide (NAD)-dependent enzymes. Their diverse cellular roles have drawn attention, especially in the context of cancer.

For instance, class I and II HDACs exhibit oncogenic properties, whereas class III plays dual roles-both promoting and suppressing tumors. HDAC11, the sole representative of class IV, functions similarly to an oncoprotein.

HDAC overexpression, common in cancers, influences breast cancer progression and prognosis, although the exact mechanisms remain unclear. Variances in their prognostic significance might stem from differing patient demographics, therapeutic approaches, or cancer stages.

HDACs are pivotal in the EMT process in breast cancer. They modulate gene expressions, impacting cell differentiation and treatment outcomes.

Additionally, HDACs have a hand in modulating ER signaling. They exhibit a dual role: suppressing ER pathways while simultaneously interacting with them.

Tamoxifen resistance—a frequently used breast cancer treatment—occurs in about half of the ER-positive tumors, suggesting that HDAC targeting could counteract this resistance.

Another significant aspect of HDACs in cancer management lies in addressing treatment resistance. Some cancers demonstrate radioresistance linked to HDACs, suggesting HDAC inhibitors could enhance radiotherapy's efficacy.

Class I HDACs, especially HDAC1/2/3, are recognized for attenuating estrogen signaling. Consequently, research might concentrate on these HDACs for advanced breast cancers. HDAC5's role in tamoxifen resistance suggests potential class II HDAC inhibitor development.

The effectiveness of vorinostat and entinostat in TNBC is underlined by lab results, warranting in vivo investigations.

Recognizing the interplay between epigenetic and genetic mechanisms can refine therapeutic strategies. Dual inhibitors, like fimepinostat, could be groundbreaking in overcoming treatment resistance.

Conclusions

Breast cancers, classified into specific subtypes, exhibit epigenetic diversity influencing their aggression and treatment response. Targeting enzymes causing these epigenetic shifts may hinder breast cancer growth.

This approach could overcome resistance to standard treatments and promote tumor differentiation. Studying these enzymes further can enhance personalized breast cancer treatments.

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    

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