The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion

Bogan, Danielle; Meile, Lucio; Bastawisy, Ahmed El; Yousef, Hend F.; Zekri, Abdel‐Rahman N.; Bahnassy, Abeer A.; ElShamy, Wael M.

doi:10.1186/s12885-017-3283-8

Cited by 13 publications

(13 citation statements)

References 44 publications

(46 reference statements)

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“…In the current study, triple negative breast cancer was significantly more prevalent among familial breast cancer cases. These findings were in agreement with a study conducted in Egypt, (27) which reported that triple negative breast cancer is commonly overexpressed in cases with positive family history compared to cases with negative family history. Also, Aysola et al (28) stated that triple negative breast cancer accounts for 15% of all breast cancer cases, with worst prognoses in young African American women.…”

Section: Resultssupporting

confidence: 93%

Effect of Family History on Clinical and Pathological Characteristics of Breast Cancer: a Hospital-Based Study in Egypt

Khalil

2017

The Egyptian Family Medicine Journal

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Background: Breast cancer is the most common female malignancy. The family history of breast cancer increases the risk of the disease. Objectives: To assess the frequency of familial breast cancer among breast cancer patients attending oncology outpatient clinics in Menoufia University Hospital and to compare the clinical and pathological characteristics of familial and sporadic breast cancer. Methods: The study was conducted on 150 women with familial or sporadic breast cancer who were attending oncology outpatient clinics, Menoufia University Hospital for follow up or receiving treatment. The participants were interviewed by predesigned questionnaire to assess risk factors for breast cancer. Data on different characteristics of the tumors were gathered from patients' medical records. Results: Familial cases represented 18.7% of studied breast cancer patients. The age of onset seems to be younger in familial breast cancers (P=0.008). Percentage of familial breast cancer cases was significantly more prevalent among premenopausal females (P=0.007). Percentage of studied cases who breastfed their babies, had bilateral breast cancer, had triple negative breast cancer and with larger tumor size (T4) was significantly more prevalent among familial than sporadic breast cancer cases (P=0.023, 0.006, 0.000, 0.000 respectively). About 63% of sporadic cases were among hormonal contraceptive users versus 43% in familial group (P=0.040). There was no significant difference between familial and sporadic groups regarding histological type was observed. Conclusion: Familial cases represented 18.7% of studied breast cancer patients. Familial breast cancer seems to affect premenopausal young women and tends to present at the larger size, bilateral and triple negative tumors.

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Section: Resultssupporting

confidence: 93%

Effect of Family History on Clinical and Pathological Characteristics of Breast Cancer: a Hospital-Based Study in Egypt

Khalil

2017

The Egyptian Family Medicine Journal

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“…IRISOE induces triple negative phenotype in human [ 53 ], and pre-clinical orthotopic mouse model [ 29 , 31 ] breast cancers. Indeed, cells overexpressing IRIS show many of the properties of TNBC cells, including high expression of the basal-biomarkers, EMT-inducers, and stemness-enforcers, as well as low expression of the BRCA1 protein, in culture [ 30 , 31 ], orthotopic mammary tumors [ 29 , 30 ], as well as human tumor samples [ 53 ]. Like human TNBC tumors, IRISOE-induced orthotopic mammary tumors show a large central acellular core of necrosis surrounded by hypoxic area [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment

et al. 2017

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Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionally defined as the necrotic/hypoxic core of the tumor, in which metabolically stressed, hypoxic, and inflamed IRISOE TNBC cells secrete higher levels of cytokines, chemokines and growth factors. One cytokine; IL-1β attracts mesenchymal stem cells (MSCs) to the niche and activates them to secrete CXCL1 that entrains IRISOE cells to secrete higher levels of CCL2 and VEGF. CCL2 attracts macrophages (TAMs) to the niche and activates them to secrete S100A8, and VEGF attracts endothelial cells (ECs) and activates them to secrete IL-8. In concert, CXCL1, S100A8 and IL-8 entrain aggressiveness in IRISOE TNBC cells within the niche. Indeed, compared to IRISOE cells alone, tumors developed by co-injecting IRISOE cells admixed with MSCs (10:1) in athymic mice were bigger and more aggressive. They contained more TAMs and ECs, expressed higher-levels of basal, epithelial to mesenchymal transition, and stemness biomarkers, quickly progressed to lymph-node or visceral metastases, and were highly sensitive to the IL-1β inhibitor “Anakinra”. Our findings supported by human data show that breast cancer patients with high-levels of IL-1β, CXCL1, CCL2, S100A8, VEGF, and IL-8 would show worse clinical outcomes. Our findings argue that this cytokine set is a diagnostic biomarker for patients who may benefit from an IRIS inhibitor-based therapy, and is a blue print for translation of approaches to combining that therapy with inhibitors of these bidirectional interactions to overcome TNBC metastasis.

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Section: Brca1-irismentioning

confidence: 99%

“…Unlike the full-length BRCA1, BRCA1-IRIS promotes the formation of aggressive and invasive breast cancers (65)(66)(67). In patients with triple-negative breast cancer (TNBC), high expression of BRCA1-IRIS correlates with aggressive clinical behavior of breast cancer, including lymph node metastasis, local recurrence, distant metastasis, and decreased survival (66,67). Both in vitro cell studies and in vivo xenograft mice models demonstrate that BRCA1-IRIS overexpression promotes TNBC tumor formation, invasion, and migration (62,(66)(67)(68)(69)(70)(71).…”

Section: Brca1-irismentioning

confidence: 99%

“…In patients with triple-negative breast cancer (TNBC), high expression of BRCA1-IRIS correlates with aggressive clinical behavior of breast cancer, including lymph node metastasis, local recurrence, distant metastasis, and decreased survival (66,67). Both in vitro cell studies and in vivo xenograft mice models demonstrate that BRCA1-IRIS overexpression promotes TNBC tumor formation, invasion, and migration (62,(66)(67)(68)(69)(70)(71). The proposed mechanism is that BRCA1-IRIS may increase DNA replication and cell proliferation (44), induce transcription of oncogenes cyclin D1 and EGFR (69, 71, 72), suppress full-length BRCA1 expression (62), activate WIP1 phosphatase (73,74), enhance EMT (epithelialmesenchymal transition), upregulate transcription factors associated with stemness, and activate the tumor-initiating cells (TIC) phenotype in TNBC cells (62).…”

Section: Brca1-irismentioning

confidence: 99%

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BRCA1—No Matter How You Splice It

Harlan-Williams

Kumaraswamy

et al. 2019

Cancer Research

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BRCA1 (breast cancer 1, early onset), a well-known breast cancer susceptibility gene, is a highly alternatively spliced gene. BRCA1 alternative splicing may serve as an alternative regulatory mechanism for the inactivation of the BRCA1 gene in both hereditary and sporadic breast cancers, and other BRCA1-associated cancers. The alternative transcripts of BRCA1 can mimic known functions, possess unique functions compared with the full-length BRCA1 transcript, and in some cases, appear to function in opposition to full-length BRCA1. In this review, we will summarize the functional "naturally occurring" alternative splicing transcripts of BRCA1 and then discuss the latest next-generation sequencing-based detection methods and techniques to detect alternative BRCA1 splicing patterns and their potential use in cancer diagnosis, prognosis, and therapy.

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The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion

Cited by 13 publications

References 44 publications

Effect of Family History on Clinical and Pathological Characteristics of Breast Cancer: a Hospital-Based Study in Egypt

Effect of Family History on Clinical and Pathological Characteristics of Breast Cancer: a Hospital-Based Study in Egypt

A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment

BRCA1—No Matter How You Splice It

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