Abstract 278: Deciphering circular RNA axes in early-onset breast cancer using a breast epithelial risk-progression 3D culture model

Lack of efficacy and a low overall success rate of phase I-II clinical trials are the most common failures when it comes to advancing cancer treatment. Current drug sensitivity screenings present several challenges including differences in cell growth rates, the inconsistent use of drug metrics, and the lack of translatability. Here, we present a patient-derived 3D culture model to overcome these limitations in breast cancer (BCa). The human plasma-derived 3D culture model (HuP3D) utilizes patient plasma as the matrix, where BCa cell lines and primary BCa biopsies were grown and screened for drug treatments. Several drug metrics were evaluated from relative cell count and growth rate curves. Correlations between HuP3D metrics, established preclinical models, and clinical effective concentrations in patients were determined. HuP3D efficiently supported the growth and expansion of BCa cell lines and primary breast cancer tumors as both organoids and single cells. Significant and strong correlations between clinical effective concentrations in patients were found for eight out of ten metrics for HuP3D, while a very poor positive correlation and a moderate correlation was found for 2D models and other 3D models, respectively. HuP3D is a feasible and efficacious platform for supporting the growth and expansion of BCa, allowing high-throughput drug screening and predicting clinically effective therapies better than current preclinical models.

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Breast Cancer Cells Induce a Pro-inflammatory Response to Mitigate Immune Mediation in a 3D Culture Model

Anticancer Research ◽

10.21873/anticanres.14638 ◽

2020 ◽

Vol 40 (11) ◽

pp. 6179-6193

Author(s):

TANYA N. AUGUSTINE ◽

RAQUEL DUARTE ◽

GEOFFREY P. CANDY

Keyword(s):

Breast Cancer ◽

Inflammatory Response ◽

Cancer Cells ◽

Breast Cancer Cells ◽

3D Culture ◽

Culture Model ◽

3D Culture Model

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HER2-Associated Breast Cancer Signature Using a 3D Culture Model.

10.1158/0008-5472.sabcs-09-4146 ◽

2009 ◽

Author(s):

P. Chaluvally-Raghavan ◽

A. Zeisel ◽

W. Koestler ◽

J. Jacob-Hirsch ◽

G. Rechavi ◽

...

Keyword(s):

Breast Cancer ◽

3D Culture ◽

Culture Model ◽

3D Culture Model

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Studying biomineralization pathways in a 3D culture model of breast cancer microcalcifications

Biomaterials ◽

10.1016/j.biomaterials.2018.06.030 ◽

2018 ◽

Vol 179 ◽

pp. 71-82 ◽

Cited By ~ 10

Author(s):

Netta Vidavsky ◽

Jennie AMR. Kunitake ◽

Aaron E. Chiou ◽

Paul A. Northrup ◽

Teresa J. Porri ◽

...

Keyword(s):

Breast Cancer ◽

3D Culture ◽

Culture Model ◽

3D Culture Model

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Prognostic Breast Cancer Signature Identified from 3D Culture Model Accurately Predicts Clinical Outcome across Independent Datasets

PLoS ONE ◽

10.1371/journal.pone.0002994 ◽

2008 ◽

Vol 3 (8) ◽

pp. e2994 ◽

Cited By ~ 142

Author(s):

Katherine J. Martin ◽

Denis R. Patrick ◽

Mina J. Bissell ◽

Marcia V. Fournier

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

3D Culture ◽

Culture Model ◽

3D Culture Model

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A risk progression breast epithelial 3D culture model reveals Cx43/hsa_circ_0077755/miR-182 as a biomarker axis for heightened risk of breast cancer initiation

Scientific Reports ◽

10.1038/s41598-021-82057-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nataly Naser Al Deen ◽

Nadia Atallah Lanman ◽

Shirisha Chittiboyina ◽

Sophie Lelièvre ◽

Rihab Nasr ◽

...

Keyword(s):

Breast Cancer ◽

Gap Junction ◽

Validation Cohort ◽

3D Culture ◽

Epithelial Polarity ◽

Potential Biomarker ◽

Culture Model ◽

Cancer Initiation ◽

Cultured Epithelia ◽

Breast Epithelial

AbstractmRNA-circRNA-miRNAs axes have been characterized in breast cancer, but not as risk-assessment axes for tumor initiation in early-onset breast cancer that is increasing drastically worldwide. To address this gap, we performed circular RNA (circRNA) microarrays and microRNA (miRNA) sequencing on acini of HMT-3522 S1 (S1) breast epithelial risk-progression culture model in 3D and chose an early-stage population miRNome for a validation cohort. Nontumorigenic S1 cells form fully polarized epithelium while pretumorigenic counterparts silenced for gap junction Cx43 (Cx43-KO-S1) lose epithelial polarity, multilayer and mimic premalignant in vivo mammary epithelial morphology. Here, 121 circRNAs and 65 miRNAs were significantly dysregulated in response to Cx43 silencing in cultured epithelia and 15 miRNAs from the patient cohort were involved in epithelial polarity disruption. Focusing on the possible sponging activity of the validated circRNAs to their target miRNAs, we found all miRNAs to be highly enriched in cancer-related pathways and cross-compared their dysregulation to actual miRNA datasets from the cultured epithelia and the patient validation cohort. We present the involvement of gap junction in post-transcriptional axes and reveal Cx43/hsa_circ_0077755/miR-182 as a potential biomarker signature axis for heightened-risk of breast cancer initiation, and that its dysregulation patterns might predict prognosis along breast cancer initiation and progression.

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Oral Contraceptive Use and Risk of Early-Onset Breast Cancer in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations

Yearbook of Obstetrics Gynecology and Women s Health ◽

10.1016/s1090-798x(08)70471-5 ◽

2006 ◽

Vol 2006 ◽

pp. 269-270

Author(s):

L.P. Shulman

Keyword(s):

Breast Cancer ◽

Oral Contraceptive ◽

Early Onset ◽

Contraceptive Use ◽

Early Onset Breast Cancer ◽

Brca1 And Brca2 ◽

Oral Contraceptive Use ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107347 ◽

2021 ◽

pp. jmedgenet-2020-107347

Author(s):

D Gareth Evans ◽

Elke Maria van Veen ◽

Helen J Byers ◽

Sarah J Evans ◽

George J Burghel ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Ductal Carcinoma ◽

Cancer Genes ◽

Early Onset Breast Cancer ◽

Younger Women ◽

Pathogenic Variants ◽

Younger Age ◽

Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

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