ABSTRACT
Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype.
Subject(s)
Adaptor Proteins, Signal Transducing , Breast Neoplasms , DNA-Binding Proteins , RNA-Binding Proteins , Rad51 Recombinase , Triple Negative Breast Neoplasms , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Cycle Proteins/genetics , Cell Line, Tumor , DNA Repair/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Humans , Neoplastic Stem Cells/pathology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Rad51 Recombinase/genetics , Rad51 Recombinase/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
The aim of this study was to evaluate whether there are thyroid diseases in which breast cancer will appear later as well as the role of autoimmunity. This was a retrospective observational study. A total of 410 females (thyroid surgery and later breast cancer) and 524 females (thyroid surgery only) were compared with regard to pathological thyroid findings, thyroid hormones, thyroid autoimmunity and type of breast cancer. Thyroid autoimmunity, especially antithyroid peroxidase antibodies, significantly increased the risk of breast cancer (p < 0.01); however, this was not true for other thyroid diseases, including thyroid cancer. No variant of breast cancer was predominant, and only thyroid autoimmunity was associated with the risk of breast cancer. Further research is needed to explain the impacts of different antithyroid antibodies.
ABSTRACT
Primary breast tuberculosis is an uncommon disease, especially in nonendemic areas. Its presentation could mimic a cancer or an abscess, but this entity must be considered for differential diagnosis in women coming from endemic countries.
ABSTRACT
The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268-79. ©2017 AACR.
