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Most breast cancers may have a luminal origin. TP53 is one of the most frequently mutated genes in breast cancers. However, how p53 deficiency contributes to breast tumorigenesis from luminal cells remains elusive. Here we report that induced p53 loss in Krt8 + mammary luminal cells leads to their clonal expansion without directly affecting their luminal identity. All induced mice develop mammary tumours with 9qA1 ( Yap1 ) and/or 6qA2 ( Met ) amplification(s). These tumours exhibit a mammary stem cell (MaSC)-like expression signature and most closely resemble claudin-low breast cancer. Thus, although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumours with loss of luminal identity. Our data also suggest that claudin-low breast cancer can develop from luminal cells, possibly via a basal-like intermediate state, although further study using a different luminal promoter is needed to fully support this conclusion. Several breast cancers may originate from mammary luminal cells and inactivating mutations of p53 are present in most triple-negative breast cancers. Here, the authors show that loss of p53 from luminal cells in mice results in their clonal expansion and mammary tumour formation.

Fibrous dysplasia (FD) is a benign bone disorder, in which normal bone structure is replaced by fibrous connective tissue. Polyostotic FD is also related to McCune-Albright syndrome with possible endocrine disorder and Cafe-au-lait macules. Although FD commonly presents as craniofacial bone abnormality, atypical presentation can be misleading and pose a difficulty in clinical diagnosis. Here we report a case of polyostotic FD, who presented as an accidental finding of multiple spinal osseous lesions, leading to clinic workup for metastatic cancer.

Background The inhibition of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway has been shown to be an effective targeted therapy in fighting both solid organ cancers and hematological malignancies. PD-L1 expression also serves as a prognostic marker in various cancers. However, the expression of PD-L1 and its prognostic significance in multiple myeloma remains largely unknown. Methods Immunohistochemistry staining of PD-L1 was performed in bone marrow biopsy samples (total of 85 samples) in 32 myeloma patients receiving autologous stem cell transplant (ASCT) at various time points: before ASCT, post-ASCT, and/or at relapse after ASCT. More than 1% of myeloma cells with PD-L1 staining was considered a positive expression of PD-L1. A correlation analysis was performed between post-ASCT overall survival (OS) and the status of PD-L1 expression. Results In this pilot study, a total of 11 patients (34%) out of our cohort (32 patients) were positive for PD-L1 expression at least once during the course of the disease. A dynamic change of PD-L1 expression was noted in three patients converting from negative (before ASCT) to positive (post-ASCT) and two patients converting from positive (before ASCT) to negative (post-ASCT). Patients with positive PD-L1 expression persisting or occurring post-ASCT had shorter post-ASCT overall survival than those with negative PD-L1 expression post-ASCT (median survival: 13 vs 23 months, p<0.05). No significant differences were detected in the known prognostic factors between these two groups at the time of ASCT. Pre-transplant PD-L1 expression status, however, showed no significant impact on post-ASCT overall survival. Furthermore, a few patients switching from positive PD-L1 expression before ASCT to negative PD-L1 expression post-ASCT had a relatively good post-ASCT overall survival (n=2, overall survival of 29 and 56 months, respectively). Conclusion Immunohistochemistry can be reliably used for measuring PD-L1 expression in decalcified marrow core biopsy materials. Our results suggest that positive PD-L1 expression persisting/occurring post-ASCT could be an adverse prognostic marker for post-ASCT OS. Additionally, PD-L1 expression appears to be dynamic and is subjected to change after ASCT. Our findings suggest that periodically monitoring PD-L1 expression in patients with multiple myeloma post-ASCT is warranted. Further studies are needed to confirm our initial observation and to evaluate if timely intervention with PD-L1 blockade can improve post-ASCT outcomes in myeloma patients.

LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite functions remain largely elusive. By characterizing its role in luminal breast epithelial cells, here we show that inhibition of LSD1 by both genetic and pharmacological approaches increases their invasion and migration, whereas its inhibition by genetic approach, but not by pharmacological approach, impairs their proliferation/survival. Induced loss of LSD1 in luminal cells in a mouse model of luminal breast cancer, MMTV-PyMT , leads to a profound increase in lung metastasis. Mechanistically, LSD1 interacts with GATA3, a key luminal-specific transcription factor (TF), and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression. It also represses expression of TRIM37 , a breast epithelial oncogene encoding a histone H2A ubiquitin ligase, and ELF5 , a key TF gene for luminal progenitors and alveolar luminal cells. LSD1-loss also leads to reduced expression of several cell–cell adhesion genes (e.g., CDH1 , VCL , CTNNA1 ), possibly via TRIM37 -upregulation and subsequently TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the oncogenic program associated with LSD1-inhibition may be suppressed via TRIM37-inhibition.

Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni syndrome). The tumors represent the basal-like subtype which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere-forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein (Trp53). Limiting dilution transplantation also showed a 3.3-fold increase in the frequency of long-term regenerative mammary stem cells in Trp53-/- mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. The effects of p53 on progenitor cells were also observed in TM40A cells using both mammosphere-forming assays and the DsRed-let7c-sensor. The frequency of long-term label-retaining epithelial cells (LRECs) was decreased in Trp53-/- mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Treatment with an inhibitor of γ-secretase (DAPT) reduced the number of Trp53-/- mammospheres to the level found in Trp53+/+ cells. These results demonstrate that basal levels of p53 restrict mammary stem/progenitor cells. Notch is a target of γ-secretase suggesting that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells. The expansion of p53-deficient mammary stem/progenitor cells can also be reversed after the expression of C-terminal p53, suggesting that the C-terminal domains of p53 may be responsible for the regulation of mammary stem/progenitor cells self-renewal. In parous mammary gland, increased p53 responsiveness sensitized mammary stem/progenitor cells to ionizing radiation without affecting the self-renewal of these cells, which may be responsible for the parity-induced protection against breast cancer.

Background Transforming growth factor beta (TGFβ) is transiently increased in the mammary gland during involution and by radiation. While TGFβ normally has a tumour suppressor role, prolonged exposure to TGFβ can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFβ during involution to determine the persistent effects on premalignant mammary epithelium. Method CDβGeo cells, a transplantable mouse mammary epithelial cell line, were treated in vitro for 14 days with TGFβ (5 ng/ml). The cells were passaged for an additional 14 days in media without TGFβ and then assessed for markers of EMT and transformation. Results The 14-day exposure to TGFβ induced EMT and transdifferentiation in vitro that persists after withdrawal of TGFβ. TGFβ-treated cells are highly tumorigenic in vivo , producing invasive solid de-differentiated tumours (100%; latency 6.7 weeks) compared to control (43%; latency 32.7 weeks). Although the TGFβ-treated cells have initiated a persistent EMT program, the stem cell population was unchanged relative to the controls. The gene expression profiles of TGFβ-treated cells demonstrate de-differentiation with decreases in the expression of genes that define luminal, basal and stem cells. Additionally, the gene expression profiles demonstrate increases in markers of EMT, growth factor signalling, TGFβ2 and changes in extra cellular matrix. Conclusion This model demonstrates full oncogenic EMT without an increase in stem cells, serving to separate EMT markers from stem cell markers.

Tissue stem cells often exhibit developmental stage-specific and sexually dimorphic properties, but the underlying mechanism remains largely elusive. By characterizing IGF1R signaling in hematopoietic cells, here we report that its disruption exerts sex-specific effects in adult hematopoietic stem and progenitor cells (HSPCs). Loss of IGF1R decreases the HSPC population in females but not in males, in part due to a reduction in HSPC proliferation induced by estrogen. In addition, the adult female microenvironment enhances engraftment of wild-type but not Igf1r-null HSPCs. In contrast, during gestation, when both female and male fetuses are exposed to placental estrogens, loss of IGF1R reduces the numbers of their fetal liver HSPCs regardless of sex. Collectively, these data support the interplay of IGF1R and estrogen pathways in HSPCs and suggest that the proliferation-promoting effect of estrogen on HSPCs is in part mediated via IGF1R signaling.Tissue stem cells often exhibit developmental stage-specific and sexually dimorphic properties, but the underlying mechanism remains largely elusive. By characterizing IGF1R signaling in hematopoietic cells, here we report that its disruption exerts sex-specific effects in adult hematopoietic stem and progenitor cells (HSPCs). Loss of IGF1R decreases the HSPC population in females but not in males, in part due to a reduction in HSPC proliferation induced by estrogen. In addition, the adult female microenvironment enhances engraftment of wild-type but not Igf1r-null HSPCs. In contrast, during gestation, when both female and male fetuses are exposed to placental estrogens, loss of IGF1R reduces the numbers of their fetal liver HSPCs regardless of sex. Collectively, these data support the interplay of IGF1R and estrogen pathways in HSPCs and suggest that the proliferation-promoting effect of estrogen on HSPCs is in part mediated via IGF1R signaling.

The ecological environment and economic development are double-edged swords. Nevertheless, we can still achieve green and coordinated development through environmental regulations and industrial agglomeration. Based on the panel data from 269 cities in China from 2008 to 2017, using the SBM-DEA model, the Malmquist-Luenberger (ML) index, and the spatial Durbin model (SDM) under different weight matrices, this paper explored the spatial pattern of ecological efficiency, the internal evolution mechanism, and the spillover effects of industrial agglomeration and environmental regulation on ecological efficiency. The results demonstrated that China’s urban ecological efficiency had an obvious spatial pattern of “high in the east and low in the west.” Due to the different life cycles of cities, the internal evolution mechanism of urban ecological efficiency had significant differences. Pure technological efficiency (PEFFCH), technological progress (TECH), and scale efficiency (SECH) have contributed the most to the ecological efficiency of the eastern, central, and western regions, respectively. Furthermore, a significant U-shaped relationship existed between industrial agglomeration and ecological efficiency. In particular, urban ecological efficiency will be improved when the industrial agglomeration level exceeds a certain scale. However, the spillover effects of industrial agglomeration were more sensitive to distance factors, leading to failure of the significance test under the economic distance and asymmetric economic distance matrix. The “innovation compensation effect” of environmental regulation was greater than the “compliance cost,” which verified the applicability of the “Porter Hypothesis” in urban ecological efficiency to a certain extent. Finally, the geographical detector showed that each variable had a certain impact on the urban ecological efficiency, and the impact of the interaction term was greater than that of a single variable.

The purpose of the “Made in China 2025” strategy is to enhance the innovation capabilities of the local manufacturing industry and achieve green and sustainable development. The role of innovation in the development of manufacturing is a hotspot in academic research, though only a few studies have analyzed the interaction between green technology manufacturing efficiency and its external innovation capabilities. This study used the 2011–2017 Chinese A-share listed manufacturing companies as samples to discuss whether regional innovation capabilities can promote the improvement of green technology manufacturing efficiency. The results showed that a significant spatial correlation between regional innovation capability and green technology manufacturing efficiency was prevalent within spatial heterogeneous bounds. In addition, regional innovation capability directly promoted the effective manufacturing of green technology efficiency, which was strongest in the eastern region of the country. Regional innovation capabilities also had a positive effect on human capital and government revenue, thereby further enhancing the green technology efficiency of manufacturing through the intermediary effect. Based on the above conclusions, some policy recommendations are put forward to facilitate the improvement of China’s regional innovation capabilities in terms of green technology efficiency in manufacturing.

Promoting green technology innovation (GTI) through environmental regulation is a key measure in reducing the severity of environmental problems. However, the effects of formal environmental regulation (FER) and informal environmental regulation (IER) on GTI have not been clarified. Through theoretical analysis, this paper analyzes the effects of FER and IER on GTI based on OLS and GTWR models. The results show the following: (1) In all Chinese cities, both FER and IER have had a positive impact on GTI. The impact of FER has been much stronger than that of IER. They show a linkage effect, and their interaction (TER) has had a positive impact on GTI. (2) In terms of spatial heterogeneity, the impact of FER, IER, and TER on GTI has decreased across the east–west gradient and has been supplemented by a core–periphery structure. (3) In terms of urban heterogeneity, the impact of FER, IER, and TER has decreased with the size of the city. This study has the potential to strengthen the effect of environmental regulation on GTI. It can provide a decision-making reference for cities to coordinate FER and IER strategies, and provides evidence for adopting regionally differentiated environmental regulation strategies.