The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs.

Triple-negative breast cancer (TNBCs) display lung metastasis tropism. However, the mechanisms underlying this organ-specific pattern remains to be elucidated. We sought to evaluate the utility of blocking extravasation to prevent lung metastasis. To identify potential geminin overexpression-controlled genetic drivers that promote TNBC tumor homing to lungs, we used the differential/suppression subtractive chain (D/SSC) technique. A geminin overexpression-induced lung metastasis gene signature consists of 24 genes was discovered. We validated overexpression of five of these genes (LGR5, HAS2, CDH11, NCAM2, and DSC2) in worsening lung metastasis-free survival in TNBC patients. Our data demonstrate that LGR5-induced ß-catenin signaling and stemness in TNBC cells are geminin-overexpression dependent. They also demonstrate for the first-time expression of RSPO2 in mouse lung tissue only and exacerbation of its secretion in the circulation of mice that develop geminin overexpressing/LGR5+-TNBC lung metastasis. We identified a novel extravasation receptor complex, consists of CDH11, CD44v6, c-Met, and AXL on geminin overexpressing/LGR5+-TNBC lung metastatic precursors, inhibition of any of its receptors prevented geminin overexpressing/LGR5+-TNBC lung metastasis. Overall, we propose that geminin overexpression in normal mammary epithelial (HME) cells promotes the generation of TNBC metastatic precursors that home specifically to lungs by upregulating LGR5 expression and promoting stemness, intravasation, and extravasation in these precursors. Circulating levels of RSPO2 and OPN can be diagnostic biomarkers to improve risk stratification of metastatic TNBC to lungs, as well as identifying patients who may benefit from therapy targeting geminin alone or in combination with any member of the newly discovered extravasation receptor complex to minimize TNBC lung metastasis.

Confronting the impact of teen pregnancy in Mississippi: the need for after-school programs.

Although rates have decreased 8% since 2014, teen pregnancy remains a substantial public health and social problem in Mississippi and elsewhere in the US. Evidence suggests that, among teenagers, the after-school hours from 3 to 6 pm are peak times of risky sexual activity. This paper reviews recent research and programs concerning sexual risk behavior among adolescents and proposes that after-school programs would increase the daily period of supervised activity and thereby reduce risks not only of pregnancy and sexually transmitted diseases but would also serve to enhance scholastic attainment and hence career prospects for the future. After-school programs from 3 to 6 p.m. should incorporate a multifaceted model that includes academic enhancement and recreational activities as well as curriculum-based sex education, youth development, and service learning.

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

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-1ß 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-1ß inhibitor "Anakinra". Our findings supported by human data show that breast cancer patients with high-levels of IL-1ß, 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.

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

BACKGROUND: Breast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt. METHODS: To reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients' tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes. RESULTS: 96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local recurrence/distant metastasis after surgery (p = 0.0028) were more pronounced in TNBC patients with BRCA1-IRIS-overexpressing tumors compared to non-TNBC patients. Finally, decreased disease-free survival in TNBC/BRCA1-IRIS-overexpressing patients compared to TNBC/BRCA1-IRIS-negative patients, and decreased overall survival in TNBC as well as non-TNBC patients was driven by BRCA1-IRIS overexpression. CONCLUSIONS: TNBC/BRCA1-IRIS-overexpressing tumors are more aggressive than TNBC/BRCA1-IRIS-negative or non-TNBC/BRCA1-IRIS-overexpressing or both negative tumors. Further studies are warranted to define whether BRCA1-IRIS drives the early TNBC lesions growth and dissemination and whether it could be used as a diagnostic biomarker and/or therapeutic target for these lesions at an early stage setting.

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

[This corrects the article DOI: 10.18632/oncotarget.20892.].