Despite new therapies, breast cancer continues to be the second leading cause of cancer mortality in women a consequence of recurrence and metastasis. In recent years, a population of cancer cells has been identified, called cancer stem cells (CSCs) with self-renewal capacity, proposed to underlie tumor recurrence and metastasis. We previously showed that the adipose tissue cytokine LEPTIN, increased in obesity, promotes the survival of CSCs in vivo. Here, we tested the hypothesis that the Leptin Receptor (LEPR), expressed in mammary cancer cells, is necessary for maintaining CSC-like and metastatic properties. We silenced LEPR via shRNA lentivirus transduction and determined that expression of stem cell self-renewal transcription factors NANOG, SOX2, and OCT4 are inhibited. LEPR-NANOG signaling pathway is conserved between species because we can rescue NANOG expression in human LEPR-silenced cells with the mouse LepR. Using a NANOG promoter GFP reporter, we showed that LEPR is enriched in NANOG promoter active (GFP+) cells. Using lineage tracing, we showed that the GFP+ cells exhibit symmetric and asymmetric division and cell death. LEPR silenced MDA-MB-231 cells exhibit a mesenchymal to epithelial transition morphologically, increased E-CADHERIN and decreased VIMENTIN expression compared to control cells. Finally, LEPR silenced cells exhibit reduced cell proliferation, self-renewal in tumorsphere assays, and tumor outgrowth in xenotransplant studies. Given the emergence of NANOG as a pro-carcinogenic protein in multiple cancers, these studies suggest that inhibition of LEPR may be a promising therapeutic approach to inhibit NANOG and thereby neutralize CSC functions.
The tumor microenvironment (TME) is a dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphological and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAGs) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an increased number of Lin−CD24+/CD49+ enriched mammary gland stem cells (MaSCs), suggesting deregulated tissue homeostasis in TAGs. Comparative transcriptome analysis of TAGs and contralateral control glands coupled with meta-analysis on differentially expressed genes with two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1. Knockdown of STAT1 in cancer-associated fibroblast (CAFs) co-cultured with human breast cancer cells altered cancer cell proliferation, indicating a role for STAT1 as a stromal contributor of tumorigenesis. Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progression in vivo. Lastly, co-treatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Taken together, these results demonstrate that stromal STAT1 expression promotes tumor progression and is a potential therapeutic target for breast cancer.
This study assessed the relationship between ethnicity, social determinants of health (SDH), and measures of health outcomes for children during the COVID-19 pandemic. This retrospective study reviewed electronic medical records of 1234 in-person well child visits (WCVs for age <18 years) at a single academic primary care clinic in a Chicago suburb for the results of SDH screening in the domains of food, financial, and transportation insecurity. The association between ethnicity, unmet SDH domains, routine medical care delay, vaccine delays, and utilization of acute and emergency department (ED) visits were evaluated. Patients with unmet SDH were more likely to be non-White ( P < .001), ≥3 years of age ( P < .001) and have Medicaid coverage ( P < .001). Unmet social needs were also associated with more acute visits ( P < .001), ED visits ( P < .001), and WCV delays ( P < .001). The results suggest that the COVID-19 pandemic has disproportionately affected patients with unmet SDH in obtaining routine pediatric well child care.
e19229 Background: Although second-opinion (SO) seeking is common in the field of oncology, there is limited empirical research on its drivers and consequences. This study’s objective is to compare the demographic and tumor characteristics between patients with newly diagnosed breast cancer who seek out SOs for treatment planning purposes with those who do not. Methods: This retrospective study includes women with newly diagnosed breast cancer who attended a single academic cancer center between 2017 and 2018 for an initial treatment consultation. Data elements were extracted from the medical record. Characteristics of first opinion and SO seekers were compared using descriptive statistics and chi-square testing. Multivariate logistic regression was used to identify predictors of SO seeking. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated. Results: Of the 547 newly diagnosed patients, 147 (26.8%) were SO seekers. Compared to those seeking a first opinion, SO seekers were statistically significantly more likely to be younger and White and to have multiple primary (versus single) tumors, and have more advanced stage (II-IV) tumors. The two groups did not differ in terms of marital status, insurance, tumor grade, and tumor hormone receptor status. In the multivariate analysis, age, race/ethnicity, and tumor stage remained statistically significant. Compared to those age 65 and older, those age <54 (OR=2.28; 95% CI:1.38-3.79) and those age 55-64 (OR=1.83; 95% CI:1.10-3.06) had a higher odds of seeking a SO. Compared to White women, Black (OR=0.33; 95% CI:0.18-0.63) and Hispanic women (OR=0.51; 95% CI:0.25-1.05) had a lower odds of SO seeking. Women with advanced stage tumors (OR=1.86; 95% CI:1.22-2.86) had a higher odds of seeking a SO compared to those with earlier stage tumors. Additionally, SO seekers had higher odds of multiple primary tumors (OR=1.63; 95% CI:0.99-2.69). Conclusions: In this study, SOs for breast cancer care were relatively common. SO seekers were more likely to be younger, White, and to have more advanced disease stage. Further analyses will include investigating the role of psychosocial factors in SO seeking and treatment changes resulting from SOs. More research on the value of SOs is needed to help guide patients and providers.
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