scholarly journals Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis

2021 ◽  
Author(s):  
Kevin Nee ◽  
Dennis Ma ◽  
Quy H. Nguyen ◽  
Nicholas Pervolarakis ◽  
Jacob Insua-Rodriguez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Hereditary Breast Cancer ◽  
Cell Communication ◽  
Bilateral Mastectomy ◽  
Epithelial Proliferation ◽  
Breast Tumorigenesis ◽  
Increased Risk ◽  
Cancer Initiation

Women with germline mutations in BRCA1 (BRCA1+/mut) have increased risk for developing hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with pre-malignant changes in the breast epithelium including altered differentiation, proliferative stress and genomic instability. However, the role of the epitheliumassociated stromal niche during BRCA1-driven tumor initiation remains unclear. Here, we show that the pre-malignant stromal niche promotes epithelial proliferation and BRCA1-driven cancer initiation in trans. Using single-cell RNAseq (scRNAseq) analysis of human pre-neoplastic BRCA1+/mut and control breast tissues, we show that stromal cells provide numerous pro-proliferative paracrine signals inducing epithelial proliferation. We identify a subpopulation of pre-cancer associated fibroblasts (pre-CAFs) that produces copious amounts of pro-tumorigenic factors including matrix metalloproteinase 3 (MMP3), and promotes BRCA1-driven tumorigenesis in vivo. Our gene-signature analysis and mathematical modeling of epithelial differentiation reveals that stromal-induced proliferation leads to the accumulation of luminal progenitor cells with altered differentiation, and thus contributes to increased breast cancer risk in BRCA1+/mut. Our results demonstrate how alterations in cell-cell communication can induce imbalances in epithelial homeostasis ultimately leading to cancer initiation. We anticipate our results to form the foundation for novel disease monitoring and therapeutic strategies to improve patient management in hereditary breast cancer. For example, pre-CAF specific proteins may serve as biomarkers for pre-cancerous disease initiation to inform whether radical bilateral mastectomy is needed. In addition, MMP inhibitors could be re-indicated for primary cancer prevention treatment in women with high-risk BRCA1 mutations.

Intention to Undergo Prophylactic Bilateral Mastectomy in Women at Increased Risk of Developing Hereditary Breast Cancer

2000 ◽  
Vol 18 (11) ◽  
pp. 2250-2257 ◽  
Author(s):  
Bettina Meiser ◽  
Phyllis Butow ◽  
Michael Friedlander ◽  
Vivienne Schnieden ◽  
Michael Gattas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Hereditary Breast Cancer ◽  
Risk Perceptions ◽  
Prophylactic Mastectomy ◽  
Bilateral Mastectomy ◽  
Increased Risk ◽  
Prophylactic Bilateral Mastectomy

PURPOSE: To assess intention to undergo prophylactic bilateral mastectomy and psychologic determinants in unaffected women at increased risk of developing hereditary breast cancer. PATIENTS AND METHODS: Three hundred thirty-three women who were awaiting their initial appointments for risk assessment, advice about surveillance, and prophylactic options at one of 14 familial cancer clinics participated in a cross-sectional, questionnaire-based survey. RESULTS: Nineteen percent of women would consider and 47% would not consider a prophylactic mastectomy, should genetic testing identify a mutation in a breast cancer–predisposing gene, whereas 34% were unsure and 1% had already undergone a prophylactic mastectomy. In a bivariate analysis, women at a moderately increased risk of developing breast cancer had the highest proportion of subjects reporting that they would consider a prophylactic mastectomy (25%), compared with women at high risk (16%) (χ2 = 7.79; P = .051). In multivariate analyses, consideration of prophylactic mastectomy strongly correlated with high levels of breast cancer anxiety (odds ratio [OR] = 17.4; 95% confidence interval [CI], 4.35 to 69.71; P = .0001) and overestimation of one’s breast cancer risk (OR = 3.01; 95% CI, 1.43 to 6.32; P = .0036), whereas there was no association with objective breast cancer risk (P = .60). CONCLUSION: A significant proportion of women at increased risk of developing hereditary breast cancer would consider prophylactic mastectomy. Although prophylactic mastectomy may be appropriate in women at high risk of developing breast cancer, it is perhaps less so in those who have a moderately increased risk. Such moderate-risk women are likely to benefit from interventions aimed at reducing breast cancer anxiety and correcting exaggerated breast cancer risk perceptions.

Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy

2021 ◽  
pp. 1-6
Author(s):  
Emma C. Dunne ◽  
Edel M. Quinn ◽  
Maurice Stokes ◽  
John M. Barry ◽  
Malcolm Kell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Core Needle Biopsy ◽  
Needle Biopsy ◽  
Demographic Data ◽  
Screening Mammography ◽  
Published Data ◽  
Epithelial Proliferation ◽  
Core Needle ◽  
In Situ Carcinoma ◽  
Increased Risk

INTRODUCTION: Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as “indeterminate” if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer. METHODS: We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses. RESULTS: In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18–145.21). CONCLUSION: Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.

scholarly journals New insights on CRISPR/Cas9-based therapy for breast Cancer

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Hussein Sabit ◽  
Shaimaa Abdel-Ghany ◽  
Huseyin Tombuloglu ◽  
Emre Cevik ◽  
Amany Alqosaibi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Research ◽  
Animal Models ◽  
Human Cancer ◽  
Step Process ◽  
Cancer Initiation ◽  
Malignant State ◽  
Treat Breast Cancer

AbstractCRISPR/Cas9 has revolutionized genome-editing techniques in various biological fields including human cancer research. Cancer is a multi-step process that encompasses the accumulation of mutations that result in the hallmark of the malignant state. The goal of cancer research is to identify these mutations and correlate them with the underlying tumorigenic process. Using CRISPR/Cas9 tool, specific mutations responsible for cancer initiation and/or progression could be corrected at least in animal models as a first step towards translational applications. In the present article, we review various novel strategies that employed CRISPR/Cas9 to treat breast cancer in both in vitro and in vivo systems.

A novel 3-D bio-microfluidic system mimicking in vivo heterogeneous tumour microstructures reveals complex tumour–stroma interactions

Lab on a Chip ◽  
2017 ◽  
Vol 17 (16) ◽  
pp. 2852-2860 ◽  
Author(s):  
Qihui Fan ◽  
Ruchuan Liu ◽  
Yang Jiao ◽  
Chunxiu Tian ◽  
James D. Farrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Invasive Breast Cancer ◽  
Stromal Cells ◽  
Breast Cancer Cells ◽  
Microfluidic System ◽  
Tumour Stroma ◽  
Collagen Hydrogel

A 3-D microfluidic system consisting of microchamber arrays embedded in a collagen hydrogel with tunable biochemical gradients was constructed for investigating interactions between invasive breast cancer cells and stromal cells.

Beyond BRCA: Review of Hereditary Syndromes Predisposing to Breast Cancer

2019 ◽  
Vol 1 (2) ◽  
pp. 84-91
Author(s):  
Jonathan V Nguyen ◽  
Martha H Thomas
Keyword(s):  
Breast Cancer ◽  
At Risk ◽  
Cancer Screening ◽  
Risk Reduction ◽  
Breast Cancer Screening ◽  
Hereditary Breast Cancer ◽  
Cancer Genes ◽  
Her Family ◽  
Increased Risk ◽  
Screening Mammograms

Abstract The majority of our hereditary breast cancer genes incur not only an increased risk for breast cancer but for other malignancies as well. Knowing whether an individual carries a pathogenic variant in a hereditary breast cancer gene can affect not only screening for the patient but for his or her family members as well. Identifying and appropriately testing individuals via multigene panels allows for risk reduction and early surveillance in at-risk individuals. Radiologists can serve as first-line identifiers of women who are at risk of having an inherited predisposition to breast cancer because they are interacting with all women receiving routine screening mammograms, and collecting family history suggestive of the presence of a mutation. We outline here the 11 genes associated with high breast cancer risk discussed in the National Comprehensive Cancer Network Genetic/Familial High-Risk: Breast and Ovarian (version 3.2019) as having additional breast cancer screening recommendations outside of annual mammography to serve as a guide for breast cancer screening and risk reduction, as well as recommendations for surveillance of nonbreast cancers.

Contralateral breast cancer and tumor recurrence in BRCA1/2 carriers and non-carriers at a high risk of hereditary breast cancer after bilateral mastectomy

2020 ◽  
Vol 98 (10) ◽  
pp. 612-617
Author(s):  
Marta Allué Cabañuz ◽  
María Domingo Bretón ◽  
Jorge Chóliz Ezquerro ◽  
María Dolores Arribas del Amo ◽  
Antonio Tomás Güemes Sánchez
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Hereditary Breast Cancer ◽  
Tumor Recurrence ◽  
Contralateral Breast Cancer ◽  
Contralateral Breast ◽  
Bilateral Mastectomy

scholarly journals Centrosome amplification: a suspect in breast cancer and racial disparities

2017 ◽  
Vol 24 (9) ◽  
pp. T47-T64 ◽  
Author(s):  
Angela Ogden ◽  
Padmashree C G Rida ◽  
Ritu Aneja
Keyword(s):  
Breast Cancer ◽  
Centrosome Amplification ◽  
Breast Cancers ◽  
Breast Tumorigenesis ◽  
Breast Cancer Outcomes ◽  
Clinically Significant ◽  
Cellular Tolerance ◽  
Cellular Phenotypes

The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN) and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extantin vitro,in vivoand clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential ‘hit’ in multistep tumorigenesis, and in some others, non-tumorigenic. However,in vivodata are limited and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes).In vitrobreast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

Effect of Density and Altered Structure of Adipose Stromal Cells on Breast Cancer Initiation.

2009 ◽  
Author(s):  
S. Ghosh ◽  
M. Walter ◽  
L. Sitai ◽  
P. Hornsby ◽  
Y. Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Adipose Stromal Cells ◽  
Cancer Initiation

Management of Women at Increased Risk for Hereditary Breast Cancer

2007 ◽  
Vol 27 (1) ◽  
pp. 51-67 ◽  
Author(s):  
Karen Lisa Smith ◽  
Claudine Isaacs
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Increased Risk

scholarly journals Cowden Syndrome Diagnosed by Bilateral Breast Cancer with Lhermitte-Duclos Disease: A Case Report

2020 ◽  
Vol 13 (1) ◽  
pp. 419-423
Author(s):  
Tamami Morisaki ◽  
Shinichiro Kashiwagi ◽  
Rika Kouhashi ◽  
Akimichi Yabumoto ◽  
Yuka Asano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Relevant Literature ◽  
Bilateral Breast Cancer ◽  
Cowden Syndrome ◽  
Thyroid Tumor ◽  
Cerebellar Hemisphere ◽  
Bilateral Mastectomy ◽  
Pten Gene ◽  
Early Detection Of Disease ◽  
Increased Risk

Cowden syndrome is extremely rare and is characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, gastrointestinal tract, breast, thyroid, and brain, and has an increased risk of breast, thyroid, and uterine cancers. Here, we report a case of Cowden syndrome diagnosed following presentation with bilateral breast cancer and provide a discussion of the relevant literature. A 47-year-old woman with a tumor in her right breast was referred to our hospital. She was diagnosed with bilateral breast cancer upon imaging and underwent a bilateral mastectomy and sentinel lymph node biopsy. Previously, she had undergone total thyroidectomy to treat a thyroid tumor. Approximately 3 years later, she was diagnosed with Lhermitte-Duclos disease affecting her left cerebellar hemisphere. As her sister and mother had also been diagnosed with breast cancer, we suspected that she might have an inherited disease. Since 80% of individuals with Cowden syndrome have a mutation in the phosphatase and tension homolog (PTEN) gene, we did not perform any genetic testing. Instead, we used the syndrome’s pathognomonic criteria and major criteria (breast cancer, thyroid tumor, and Lhermitte-Duclos disease) to diagnose our patient with Cowden syndrome. While treatment of Cowden syndrome is currently limited to strategies that can manage the symptoms, patients are at an increased risk of certain cancers and require regular screening to allow for early detection of disease.

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