Association between allostatic load and breast cancer risk: a cohort study.

BACKGROUND: Allostatic load (AL) reflects the collective load of chronic stress during lifetime. Previous studies have shown that higher AL is associated with poor clinical outcomes among breast cancer patients. However, the relationship between AL and breast cancer risk is still unclear. METHODS: To fill the gap, we analyzed the association between AL and the development of breast cancer in 181,455 women identified from the UK Biobank. RESULTS: During the follow-up from 2006 to 2020, 5,701 women were diagnosed with incident breast cancer. Significantly higher AL was observed among incident breast cancer cases than all study participants (mean: 2.77 vs. 2.63, P < 0.01). Univariate Cox regression analysis indicated the risk of breast cancer was increased by 5% per one AL unit increase (hazard ratio (HR) = 1.05, 95% confidence interval (CI) 1.04, 1.07). In multivariate analyses, after adjusting demographics, family history of breast cancer, reproductive factors, socioeconomic status, lifestyle factors, and breast cancer polygenic risk score (PRS), the significant association remained (HR = 1.05, 95%CI 1.03, 1.07). The significant relationship was further confirmed in the categorical analysis. Compared with women in the low AL group (AL: 0 ~ 2), those in the high AL group (AL: 3 ~ 11) had a 1.17-fold increased risk of breast cancer (HR = 1.17, 95%CI 1.11, 1.24). Finally, in the stratified analysis, joint effects on the risk of breast cancer were observed between the AL and selected known breast cancer risk factors, including age, family history of breast cancer, PRS, income, physical activity, and alcohol consumption. CONCLUSION: In summary, those findings have demonstrated that higher AL was associated with an increased breast cancer risk in women. This association is likely independent of known breast cancer risk factors. Thus, the AL could be a valuable biomarker to help breast cancer risk prediction and stratification.

Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma.

MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an "Achilles' heel" and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCN-amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCN-amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.

Inhibition of breast cancer metastasis suppressor 1 promotes a mesenchymal phenotype in lung epithelial cells that express oncogenic K-RasV12 and loss of p53.

Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and invasion in response to specific NSCLC driver mutations are poorly understood. To experimentally address this, we utilized immortalized human bronchial epithelial cells in which p53 was knocked down in the presence of oncogenic K-RasV12 (HBEC3-p53KD-K-RasV12). These genetic alterations are commonly found in NSCLC and are associated with a poor prognosis. To determine the importance of BRMS1 for cytoskeletal function, cell migration and invasion in our model system we stably knocked down BRMS1. Here, we report that loss of BRMS1 in HBEC3-p53KD-K-RasV12 cells results in a dramatic increase in cell migration and invasion compared to controls that expressed BRMS1. Moreover, the loss of BRMS1 resulted in additional morphological changes including F-actin re-distribution, paxillin accumulation at the leading edge of the lamellapodium, and cellular shape changes resembling mesenchymal phenotypes. Importantly, re-expression of BRMS1 restores, in part, cell migration and invasion; however it does not fully reestablish the epithelial phenotype. These finding suggests that loss of BRMS1 results in a permanent, largely irreversible, mesenchymal phenotype associated with increased cell migration and invasion. Collectively, in NSCLC cells without p53 and expression of oncogenic K-Ras our study identifies BRMS1 as a key regulator required to maintain a cellular morphology and cytoskeletal architecture consistent with an epithelial phenotype.

BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300.

The mechanisms through which the metastasis suppressor gene BRMS1 functions are poorly understood. Herein, we report the identification of a previously undescribed E3 ligase function of BRMS1 on the histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation. We identify BRMS1 as the first eukaryote structural mimic of the bacterial IpaH E3 ligase family and establish that the evolutionarily conserved CXD motif located in BRMS1 is responsible for its E3 ligase function. Mutation of this E3 ligase motif not only abolishes BRMS1-induced p300 polyubiquitination and degradation, but importantly, dramatically reduces the metastasis suppressor function of BRMS1 in both in vitro and in vivo models of lung cancer metastasis.

DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria.

Mitochondrial DNA (mtDNA) has been reported to contain 5-methylcytosine (5mC) at CpG dinucleotides, as in the nuclear genome, but neither the mechanism generating mtDNA methylation nor its functional significance is known. We now report the presence of 5-hydroxymethylcytosine (5hmC) as well as 5mC in mammalian mtDNA, suggesting that previous studies underestimated the level of cytosine modification in this genome. DNA methyltransferase 1 (DNMT1) translocates to the mitochondria, driven by a mitochondrial targeting sequence located immediately upstream of the commonly accepted translational start site. This targeting sequence is conserved across mammals, and the encoded peptide directs a heterologous protein to the mitochondria. DNMT1 is the only member of the three known catalytically active DNA methyltransferases targeted to the mitochondrion. Mitochondrial DNMT1 (mtDNMT1) binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix. mtDNMT1 expression is up-regulated by NRF1 and PGC1α, transcription factors that activate expression of nuclear-encoded mitochondrial genes in response to hypoxia, and by loss of p53, a tumor suppressor known to regulate mitochondrial metabolism. Altered mtDNMT1 expression asymmetrically affects expression of transcripts from the heavy and light strands of mtDNA. Hence, mtDNMT1 appears to be responsible for mtDNA cytosine methylation, from which 5hmC is presumed to be derived, and its expression is controlled by factors that regulate mitochondrial function.