Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

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Implications of Lifestyle and Occupational Factors on the Risk of Breast Cancer in Shiftwork Nurses

Healthcare ◽

10.3390/healthcare9060649 ◽

2021 ◽

Vol 9 (6) ◽

pp. 649

Author(s):

Javier Fagundo-Rivera ◽

Regina Allande-Cussó ◽

Mónica Ortega-Moreno ◽

Juan Jesús García-Iglesias ◽

Adolfo Romero ◽

...

Keyword(s):

Breast Cancer ◽

Shift Work ◽

Regression Tree ◽

Night Work ◽

Circadian Disruption ◽

Classification And Regression Tree ◽

Baseline Risk ◽

Unhealthy Lifestyle ◽

Cross Sectional ◽

Occupational Factors

Shift work that involves circadian disruption has been highlighted as a likely carcinogenic factor for breast cancer in humans. Also, unhealthy lifestyle habits observed in night work nurses could be causally related to an increase in the incidence of estrogen-positive breast tumours in this population. Assessing baseline risk of breast cancer in nurses is essential. The objective of this study was to analyze the risk of breast cancer that nurses had in relation to their lifestyle and labour factors related to shift work. A cross-sectional descriptive study through a questionnaire about sociodemographic variables, self-perception of health, and working life was designed. The sample consisted of 966 nurses. The relationship between variables was tested. A binary logistic regression and a classification and regression tree were performed. The most significant labour variables in relation to the risk of breast cancer were the number of years worked (more than 16 years; p < 0.01; OR = 8.733, 95% CI = 2.811, 27.134) and the total years performing more than 3 nights per month (10 or more years; p < 0.05; OR = 2.294, 95% CI = 1.008, 5.220). Also, the nights worked throughout life (over 500; OR = 4.190, 95% CI = 2.118, 8.287) were significant in the analysis. Nurses who had or ever had breast cancer valued their self-perceived health more negatively (p < 0.001) and referred a lower quality of sleep (p < 0.001) than the non-cases nurses. The occupational factors derived from night work could have several impacts on nurses’ health and their family-work balance. Promoting healthy lifestyles, informing about shift work risks, and adjusting shift work schedules are critical methods to decrease the possible effects of circadian disruption in nurses.

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35P Prognostic impact of cytotoxic CD4 T cells (CD4 CTL) in tumour immune microenvironment of breast cancer patients

Annals of Oncology ◽

10.1016/j.annonc.2021.03.049 ◽

2021 ◽

Vol 32 ◽

pp. S34-S35

Author(s):

K.S. Shohdy ◽

D.S. Almeldin ◽

R. Ghaly ◽

L. Kassem ◽

O. Pagani

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Patients ◽

Cd4 T Cells ◽

Prognostic Impact ◽

Breast Cancer Patients ◽

Immune Microenvironment

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Deciphering the nexus between the tumor immune microenvironment and DNA methylation in subgrouping estrogen receptor-positive breast cancer

Breast Cancer ◽

10.1007/s12282-021-01262-9 ◽

2021 ◽

Author(s):

Xiao-Qiong Chen ◽

Fan Zhang ◽

Fu-Hui Xiao ◽

Yu Peng

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Estrogen Receptor ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

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Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer

npj Breast Cancer ◽

10.1038/s41523-021-00223-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Gaia Griguolo ◽

Maria Vittoria Dieci ◽

Laia Paré ◽

Federica Miglietta ◽

Daniele Giulio Generali ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Gene Expression Data ◽

Hormone Receptor ◽

Tumor Biology ◽

Expression Data ◽

Immune Microenvironment ◽

Immune Infiltrate ◽

Hormone Receptor Positive ◽

Her2 Breast Cancer

AbstractLittle is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2− breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2− early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.

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Breast cancer and circadian disruption from electric lighting in the modern world

CA A Cancer Journal for Clinicians ◽

10.3322/caac.21218 ◽

2013 ◽

Vol 64 (3) ◽

pp. 207-218 ◽

Cited By ~ 148

Author(s):

Richard G. Stevens ◽

George C. Brainard ◽

David E. Blask ◽

Steven W. Lockley ◽

Mario E. Motta

Keyword(s):

Breast Cancer ◽

Circadian Disruption ◽

Modern World

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Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12573 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12573-e12573

Author(s):

Yoshihisa Tokumaru ◽

Masanori Oshi ◽

Vijayashree Murthy ◽

Eriko Katsuta ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Patients ◽

Immune Cells ◽

Breast Cancer Patients ◽

Immune Microenvironment ◽

High Group ◽

Anti Cancer ◽

Tumor Immune Microenvironment ◽

Er Positive

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.

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