Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance. Clin Epigenetics 2021 Sep 17;13(1):175
Date
09/19/2021Pubmed ID
34535185Pubmed Central ID
PMC8447690DOI
10.1186/s13148-021-01167-6Scopus ID
2-s2.0-85115159581 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
BACKGROUND: Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells.
METHODS: In this study, we conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. Furthermore, we performed in silico functional analysis on 3D-growth-specific looping genes and to compare patient outcomes with or without endocrinal therapy. Finally, we performed 3C/RT-qPCR validations in 3D spheroids and 3D-FISH confirmations in organoids of breast cancer patient tissues.
RESULTS: We found that chromatin structures have experienced drastic changes during the 3D culture growth of BC cells although there is not much change in the quantity of chromatin domains. We also observed that the strengths of looping genes were statistically different between 2D monolayers and 3D spheroids. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected genes in Hippo relevant pathways with enhanced looping in organoids of breast cancer patient tissues.
CONCLUSIONS: Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer. Our analyses suggest that the strengthened looping-mediated Hippo relevant pathways may contribute to endocrine therapy resistance in breast cancer patients.
Author List
Li J, Fang K, Choppavarapu L, Yang K, Yang Y, Wang J, Cao R, Jatoi I, Jin VXAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultBreast Neoplasms
Chromatin
DNA Methylation
Endocrine Disruptors
Female
Humans
Middle Aged
Spheroids, Cellular