scholarly journals Generation and characterisation of an estrogen receptor-positive GEMM-derived Pten p53 null transplantable breast tumour model for therapeutic testing

2019 ◽  
Author(s):  
E.J. Davies ◽  
H. Morgan ◽  
G. Tornillo ◽  
C.D. Chabbert ◽  
H. Kendrick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
De Novo ◽  
Breast Tumour ◽  
Genetically Engineered ◽  
Early Passage ◽  
Pharmacological Agents ◽  
Long Latency ◽  
Tumour Implantation ◽  
Estrogen Receptor Positive ◽  
Transplantable Tumour

AbstractAssessing the signalling pathway dependencies of tumours that arise autochthonously in genetically engineered mouse models (GEMMs) of breast cancer is particularly challenging due to the high degree of intra- and inter-tumour heterogeneity, as well as the long latency of tumour development in such models. Use of transplantable tumour lines derived from autochthonous tumours (‘Mouse Derived Xenografts’ or MDXs) is one possible solution and has been used successfully in models of BRCA1-associated triple negative breast cancer. However, their potential in ER+ breast cancer models has not been addressed. Here, we assess the utility of orthotopic transplantable tumour lines derived from an autochthonous ER+ Blg-cre Ptenfl/fl p53fl/fl breast cancer model. We show that initial tumour implantation and early passage results in the development of lines of progeny with heterogeneous histopathological phenotypes which is coincident with an accumulation of, or selection for, de novo mutations. Importantly, these lines also display different dependencies on the key pathways that drive tumourigenesis, which can lead to inherent resistance to treatment with pharmacological agents targeting these pathways and makes them important models to test strategies to overcome such resistance.

scholarly journals Modeling Breast Cancer Using CRISPR-Cas9–Mediated Engineering of Human Breast Organoids

2019 ◽  
Vol 112 (5) ◽  
pp. 540-544 ◽  
Author(s):  
Johanna F Dekkers ◽  
James R Whittle ◽  
François Vaillant ◽  
Huei-Rong Chen ◽  
Caleb Dawson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor Genes ◽  
De Novo ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
Patient Treatment ◽  
Normal Epithelium ◽  
Molecular Events ◽  
Estrogen Receptor Positive

Abstract Breast cancer is characterized by histological and functional heterogeneity, posing a clinical challenge for patient treatment. Emerging evidence suggests that the distinct subtypes reflect the repertoire of genetic alterations and the target cell. However, the precise initiating events that predispose normal epithelium to neoplasia are poorly understood. Here, we demonstrate that breast epithelial organoids can be generated from human reduction mammoplasties (12 out of 12 donors), thus creating a tool to study the clonal evolution of breast cancer. To recapitulate de novo oncogenesis, we exploited clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 for targeted knockout of four breast cancer–associated tumor suppressor genes (P53, PTEN, RB1, NF1) in mammary progenitor cells from six donors. Mutant organoids gained long-term culturing capacity and formed estrogen-receptor positive luminal tumors on transplantation into mice for one out of six P53/PTEN/RB1–mutated and three out of six P53/PTEN/RB1/NF1–mutated lines. These organoids responded to endocrine therapy or chemotherapy, supporting the potential utility of this model to enhance our understanding of the molecular events that culminate in specific subtypes of breast cancer.

scholarly journals High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

2021 ◽  
Author(s):  
Marta Palafox ◽  
Laia Monserrat ◽  
Meritxell Bellet ◽  
Guillermo Villacampa ◽  
Abel Gonzalez-Perez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
De Novo ◽  
Acquired Resistance ◽  
Poor Clinical Outcome ◽  
Cyclin Dependent Kinases ◽  
Estrogen Receptor Positive ◽  
Inhibitor Resistance ◽  
P16 Expression ◽  
P16 Overexpression

Abstract Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), combined with endocrine therapy (ET), have demonstrated higher antitumor activity than ET alone for the treatment of advanced estrogen receptor-positive (ER+) breast cancer (BC). Some ER+ BC are de novo resistant to CDK4/6i and others develop acquired resistance. Therapies for tumors after progression are needed. Here, we demonstrate that p16 overexpression is associated with reduced antitumor activity of CDK4/6i in patient-derived xenografts (PDX; n=37) and ER+ BC cell lines, and reduced response of early/advanced ER+HER2- BC patients (n=49) to CDK4/6i. We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome in ER+, CDK4/6i-treated BC PDX and patients. Combination of CDK4/6i ribociclib with PI3K inhibitor (PI3Ki) alpelisib showed antitumor activity in ER+ non-basal-like BC PDX, independently of PIK3CA or RB1 mutation (n=25). Our results offer new insights into predicting primary and acquired resistance to CDK4/6i and post-progression therapeutic strategies.

scholarly journals Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Esmael Besufikad Belachew ◽  
Dareskedar Tsehay Sewasew
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Therapeutic Modality ◽  
Breast Cancers ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

scholarly journals The challenges of modeling hormone receptor-positive breast cancer in mice

2018 ◽  
Vol 25 (5) ◽  
pp. R319-R330 ◽  
Author(s):  
Berna C Özdemir ◽  
George Sflomos ◽  
Cathrin Brisken
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Hormonal Regulation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Xenograft Model ◽  
Genetically Engineered ◽  
Preclinical Research

Estrogen receptor-positive (ER+) tumors account for 70–80% of all breast cancer (BC) cases and are characterized by estrogen dependency for their growth. Endocrine therapies using estrogen receptor antagonists or aromatase inhibitors represent a key component of the standard of care for these tumors. The occurrence of de novo or acquired resistance to estrogen withdrawal represents an important clinical problem, impacting on patient survival. In addition, despite an initially favorable outcome, a part of ER+ BC patients present with disease recurrence locally or at distant sites years or even decades after apparent remission. In vivo models that closely mimic human disease are urgently needed to study the biology of these tumors, investigate the molecular mechanisms underlying endocrine resistance and identify patients at risk of recurrence. Despite the similarities in the overall hormonal regulation of mammary gland development between mice and humans, the majority of the mammary carcinomas occurring in genetically engineered mouse models (GEMMs) are ER negative and most xenograft models are based on few ER+ cancer cell lines. We recently showed that the microenvironment is critical for ER+ cancer cells and discuss in this review the potential of intraductal xenograft model for basic and preclinical research.

scholarly journals Epigenetic therapy suppresses endocrine-resistant breast tumour growth by re-wiring ER-mediated 3D chromatin interactions

2021 ◽  
Author(s):  
Joanna Achinger-Kawecka ◽  
Clare Stirzaker ◽  
Kee-Ming Chia ◽  
Neil Portman ◽  
Elyssa Campbell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumour Growth ◽  
Target Genes ◽  
Three Dimensional ◽  
Therapy Resistance ◽  
Breast Tumour ◽  
Epigenetic Therapy ◽  
Dna Hypomethylation ◽  
3D Genome ◽  
Estrogen Receptor Positive

Three-dimensional (3D) epigenome remodelling is emerging as an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome cancer therapy resistance remains largely unaddressed. Here we show that treatment of endocrine-resistant estrogen receptor positive (ER+) breast cancer with an FDA-approved epigenetic therapy Decitabine (5-Aza-mC), results in genome-wide DNA hypomethylation and suppression of tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Systematic integration of matched chromatin conformation capture (Hi-C), Promoter Capture Hi-C, RNA-seq and ER ChIP-seq data revealed widespread effects on epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associating domains (TAD) boundary insulation. Key enhancer ER binding sites were demethylated and re-activated after Decitabine treatment, resulting in new ER mediated enhancer-promoter interactions and concordant activation of tumour suppressive gene pathways. Importantly, we show that the activated ER target genes were also predictive of good outcome in multiple ER+ breast cancer clinical cohorts. Together our study reveals a previously undescribed mechanism of Decitabine in re-wiring DNA methylation-dependent 3D genome architecture resulting in suppression of tumour growth, and highlights the potential of epigenetic therapy in targeting ER+ endocrine-resistant breast cancer.

Olfactomedin-like 2A, 2B and 3 are differentially expressed in breast cancer metastases.

2019 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Genetically Engineered ◽  
Differentially Expressed ◽  
Genetically Engineered Mouse Models ◽  
Breast Cancer Metastases ◽  
Multiple Datasets ◽  
Cancer Metastases ◽  
Distant Organ ◽  
Metastatic Process ◽  
Differential Gene

Differential gene expression analysis of multiple datasets, in mice and in men revealed that transcripts of the olfactomedin-like family are differentially expressed in metastases, both in patients with breast cancer and in genetically engineered mouse models of breast cancer. The expression of olfactomedin-like genes was perturbed in metastases to the bone, brain and the lung, suggesting that these molecules function in the metastatic process rather than having tissue-specific associations with the site of dissemination. The olfactomedin-like family may play a role in the progression of breast cancer from frank tumor to colonization of distant organ sites.

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