Sporadic activation of an oxidative stress-dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies

Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative stress within 3D cultures. Inhibition of NRF2 or p53 individually disrupted some of the transcripts defining the regulatory state but did not yield a notable phenotype in nontransformed breast epithelial cells. In contrast, combined perturbation prevented 3D growth in an oxidative stress–dependent manner. By integrating systems models of NRF2 and p53 signaling in a single oxidative stress network, we recapitulated these observations and made predictions about oxidative stress profiles during 3D growth. NRF2 and p53 signaling were similarly coordinated in normal breast epithelial tissue and hormone-negative ductal carcinoma in situ lesions but were uncoupled in triple-negative breast cancer (TNBC), a subtype in which p53 is usually mutated. Using the integrated model, we correlated the extent of this uncoupling in TNBC cell lines with the importance of NRF2 in the 3D growth...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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Conclusion: This article outlines the evaluation of a new program demonstrating that medical oncology practices can make improvements in the care of their underserved populations if provided with the proper tools, methods, and coaching. The use of formative evaluation methodology also identified opportunities for improvement and ultimately resulted in additional funding for more practices to participate in the program.
Source: Quality Management in Healthcare - Category: Health Management Tags: Methods and Instruments Source Type: research
Abstract: The foreign body reaction (FBR) is a well-documented immune reaction. Much of the literature on FBRs has focused on minimizing this immune response to mitigate the impact on medical implants. Here, we present a case that illustrates a serendipitous oncologic outcome from an FBR. A 54-year-old man presented with an aggressive basal cell carcinoma (BCC). At the first resection, he had broadly positive surgical margins. The surgical wound was temporized with a polyurethane wound vacuum assisted closure (VAC) device. He was lost to follow-up having retained a VAC sponge for a total of 12 weeks. A wide re-resectio...
Source: The American Journal of Dermatopathology - Category: Pathology Tags: Extraordinary Case Report Source Type: research
Abstract: Human papillomavirus (HPV) is a leading cause of cancer. Increasing HPV vaccination recommendations by primary care providers to patients decreases the burden of this viral infection. Providers need to be educated about this condition and the available options for immunization to feel confident in making strong recommendations and thereby increase HPV immunization rates.
Source: The Nurse Practitioner - Category: Nursing Tags: Feature Source Type: research
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Source: The Nurse Practitioner - Category: Nursing Tags: Department: Preventing, Treating, and Surviving Cancer Source Type: research
Diseases linked to vitamin D deficiency include cardiovascular disease, diabetes and cancer.
Source: PsyBlog | Psychology Blog - Category: Psychiatry & Psychology Authors: Tags: Nutrition Source Type: blogs
CONCLUSIONS: We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.SIGNIFICANCE: To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanis...
Source: Biology of the Cell - Category: Cytology Authors: Source Type: research
Trends Neurosci. 2021 Sep 21:S0166-2236(21)00167-3. doi: 10.1016/j.tins.2021.08.008. Online ahead of print.ABSTRACTThe initiation, progression, and metastatic spread of cancer elicits diverse changes in systemic physiology. In this way, cancer represents a novel homeostatic challenge to the host system. Here, we discuss how the hypothalamus, a critical brain region involved in homeostasis senses, integrates and responds to cancer-induced changes in physiology. Through this lens, cancer-associated changes in behavior (e.g., sleep disruption) and physiology (e.g., glucocorticoid dysregulation) can be viewed as the result of ...
Source: Trends in Neurosciences - Category: Neuroscience Authors: Source Type: research
Chem Biodivers. 2021 Sep 24. doi: 10.1002/cbdv.202100301. Online ahead of print.ABSTRACTIsorhamnetin is a natural flavonoid which shows a variety of biological activities such as antioxidant, anti-inflammation and antitumor. In order to identify the cellular binding protein of isorhamnetin as potential anti-cancer target, we first synthesized 3'- O -substituted quercetin as isorhamnetin analogues and evaluated the growth inhibitory activity of these derivatives on breast, colon and prostate cancer cell lines. The preliminary results showed that the 3'- O modification did not affect the cytotoxic activity of the scaffold. A...
Source: Chemistry and Biodiversity - Category: Biochemistry Authors: Source Type: research
CONCLUSION: Taken together, our data provide clues to the important role of menin in ERα regulation and the formation of breast cancer subtypes.PMID:34561764 | DOI:10.1007/s10549-021-06339-9
Source: Cell Research - Category: Cytology Authors: Source Type: research
Cell Res. 2021 Sep 24. doi: 10.1038/s41422-021-00565-y. Online ahead of print.ABSTRACTThe AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses n...
Source: Cell Research - Category: Cytology Authors: Source Type: research
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