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Background: Data on burden and changing trends of breast cancer are of value for policymaking. We aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017. Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study. The number of incident cases, deaths, and DALYs attributable to breast cancer are reported as well as age-standardized rates. Estimated annual percentage changes (EAPCs) in age-standardized rates were calculated to quantify the temporal trends. Moreover, the attributable burden to breast cancer risk factors was also estimated. Results: There were 1,960,682 incident cases and 611,625 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age-standardized incidence rates (ASIRs) increased between 1990 and 2017, while the age-standardized mortality rates and DALY rates decreased. The corresponding EAPCs were 0.41, −0.62, and −0.56, respectively. These trends were heterogeneous across regions and countries. The increase in the ASIRs was more prominent in countries with a low sociodemographic index. The percentages of breast cancer deaths due to alcohol use and tobacco were decreasing, while deaths due to high body mass index and high fasting plasma glucose were increasing. Conclusion: Breast cancer remained a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer should be considered at the national scale and even at the subnational scale.

Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer (TNBC), suggesting that additional immune escape mechanisms may exist. Here, we performed two-step customized in vivo CRISPR screens targeting disease-related immune genes using different mouse models with multidimensional immune-deficiency characteristics. In vivo screens characterized gene functions in the different tumor microenvironments and recovered canonical immunotherapy targets such as Ido1 . In addition, functional screening and transcriptomic analysis identified Lgals2 as a candidate regulator in TNBC involving immune escape. Mechanistic studies demonstrated that tumor cell–intrinsic Lgals2 induced the increased number of tumor-associated macrophages, as well as the M2-like polarization and proliferation of macrophages through the CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Blockade of LGALS2 using an inhibitory antibody successfully arrested tumor growth and reversed the immune suppression. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC.

Metastasis is the main death reason for triple-negative breast cancer (TNBC). Thus, identifying the driver genes associated with metastasis of TNBC is urgently needed.CRISPR screens have dramatically enhanced genome editing and made it possible to identify genes associated with metastasis. In this study, we identified and explored the crucial role of ras homolog family member V (RhoV) in TNBC metastasis. Here, we performed customized in vivo CRISPR screens targeting metastasis-related genes obtained from transcriptome analysis of TNBC. The regulatory role of RhoV in TNBC was validated using gain-or loss-of-function studies in vitro and in vivo. We further conducted immunoprecipitation and LC-MS/MS to explore the metastasis mechanism of RhoV. In vivo functional screens identified RhoV as a candidate regulator involved in tumor metastasis. RhoV was frequently upregulated in TNBC and correlated with poor survival. Knockdown of RhoV significantly suppressed cell invasion, migration, and metastasis both in vitro and in vivo. In addition, we provided evidence that p-EGFR interacted with RhoV to activate the downstream signal pathway of RhoV, thereby promoting tumor metastasis. We further confirmed that this association was dependent on GRB2 through a specific proline-rich motif in the N-terminus of RhoV. This mechanism of RhoV is unique, as other Rho family proteins lack the proline-rich motif in the N-terminus.

Poor stability is a significant challenge to organic–inorganic hybrid perovskites for practical optoelectronic applications, which results from their inherent ionic nature and soft structures. The coordination bonding strategy is supposed to be a valid approach by enhancing the interaction between the cations and inorganic frameworks. Herein, the first pair of cation‐coordinated perovskites with high stability, achieved through coordination bonds between the cations and [PbXn] anions instead of the weak hydrogen bonds and van der Waals force presented in conventional ionic perovskites, is reported. In L/R‐(4HOPD)PbBr3 (4HOPD = 4‐hydroxypiperidine cation) (L/R=Left/Right–handed), one of the six halogen atoms is replaced by an oxygen atom from the cation. The PbO bond contributes to the high stability under a double 85 test. L/R‐(4HOPD)PbBr3 crystallizes in the tetragonal system, belonging to one of 11 enantiomorphic space group types, P41212 and P43212. Similar to quartz, the chirality originates from the helical assembly of achiral units. The chirality‐induced optical rotatory power is 16.84° mm−1 at 404 nm. Moreover, the uniaxial negative birefringent property with a comparable Δn value makes it a good alternative to quartz. The remarkable stability of this new perovskite presents significant potential for further investigation into stable perovskites and their applications in optical rotation and polarizing optics.

A two-dimensional (2D) organic−inorganic hybrid perovskite (OIHP) material with out-of-plane ferroelectricity is the key to the miniaturization of vertical-sandwich-type ferroelectric optoelectronic devices. However, 2D OIHP ferroelectrics with out-of-plane polarization are still scarce, and effective design strategies are lacking. Herein, we report a novel 2D Dion−Jacobson perovskite ferroelectric semiconductor synthesized by a rigid-to-flexible cationic tailoring strategy, achieving an out-of-plane polarization of 1.7 μC/cm 2 and high photoresponse. Integrating out-of-plane ferroelectricity with excellent photoelectric properties affords a promising platform to investigate ferroelectricity-related effects in vertical optoelectronic devices.

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Here, we prospectively collected what is currently the largest Chinese breast cancer cohort of 1,143 patients for clinical sequencing and performed integrated analysis of their clinical and genomic characteristics. All samples were collected via needle biopsy. A custom-designed genetic panel was used in this study. The panel was a hybridization capture-based assay, including 484 genes that are targets of approved and experimental therapies as well as frequently mutated genes in breast cancer. The panel was designed for detecting mutations and small insertions and deletions. The highest prevalence of breast cancer-related variations observed in our Chinese cohort was TP53 mutations (53%), followed by PIK3CA (19%), NF1 (10%), GATA3 (9%) and KMT2C (9%) mutations. The hotspot mutations (with frequencies higher than 2%) in Chinese breast cancer included PIK3CA p. H1047R (10%), AKT1 p. E17K (4%), KMT2C p. K2797fs (2%) and TP53 p. R248Q (2%). PIK3CA and AKT1 mutations were found to be especially enriched in the Luminal (HER2-) subtype, NF1 and ERBB2 mutations were enriched in Luminal (HER2+) subtype, and PTEN mutations were enriched in triple negative breast cancer. In addition, there was significant disparity of mutation load among the different subtypes, suggesting a high mutation load in triple negative breast cancer. We further investigated the differences in mutational features between the Chinese cohort and foreign published cohorts, especially the TCGA and MSKCC breast cancer datasets, and revealed the distinction mainly existed in breast cancer of the HR+/HER2- subtype, while the other subtypes showed a similar mutation prevalence. We evaluated 9 canonical signaling pathways with frequent oncogenic alterations. The pathways that we analyzed included the cell cycle signaling, Hippo signaling, Notch signaling, PI-3-Kinase (PI3K) signaling, β-catenin/Wnt signaling, receptor-tyrosine (RTK)/RAS/MAP-Kinase (RTK-RAS) signaling, p53 signaling, TGF-β signaling and Myc signaling pathways. Alterations in the RTK-RAS pathway were exclusive to those in the PI3K pathway in hormone receptor (HR)-positive breast cancer and co-occurred with those in the Notch pathway in human epidermal growth factor receptor-2 (HER2)-positive, HR- and HER2-positive breast cancer. PI3K signaling pathway mutations were identified as a driving factor, and our finding revealed the competitively oncogenic role of mutations in the RTK-RAS pathway, especially in the HR+/HER2- subtype. Furthermore, we identified mutations in the P53 (53% versus 31%, p < 0.001), RTK-RAS (31% versus 18%, p < 0.001), Notch (17% versus 11%, p < 0.001), WNT (7% versus 1%, p < 0.001) and Hippo (2% versus 0%, p < 0.001) pathways that were more prevalent in our Chinese cohort than in the Caucasian cohort. We further explored the potential actionable targets in Chinese patients with breast cancer who might benefit from our sequencing. The OncoKB classification system was used to stratify levels of genomic biomarkers in the different subtypes. Over 32% of breast cancer patients could be genomically matched to at least one actionable biomarker. Notably, NF1 and NOTCH1 mutations were markedly enriched in Chinese patients, suggesting the potential for novel treatment strategies for breast cancer. Taken together, our study comprehensively revealed the characteristics of mutations in Chinese breast cancer, improving our understanding of the mutational diversity among different molecular subtypes, identifying potential treatment biomarkers and leading to systematic genomic studies and novel clinical trials. Citation Format: Guan-Tian Lang, Jin-Xiu Shi, Yi-Zhou Jiang, Xiao-Guang Li, Yu-Chen Pei, Fang-Lin Zhang, Chen-Hui Zhang, Ding Ma, Yi Xiao, Ke-Da Yu, Peng-Chen Hu, Ming-Liang Jin, Hai Wang, Yun-Song Yang, Xuan Luo, Qi Hong, Feng Qiao, Wei-Li Sun, Meng-Zhu Xue, Shi-Ping Li, A-Yong Cao, Zhong-Hua Wang, Jia-Xin Zhang, Gen-Hong Di, Peng Wang, Da-Qiang Li, Xin Hu, Wei Huang, Zhi-Ming Shao. Clinical sequencing characterizes the genomic landscape and actionable mutations of Chinese breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-01.