Background: Trastuzumab is an effective drug for the treatment of Her2-positive breast cancer. But, primary or secondary resistances to trastuzumab have become an important factor influencing the curative effect. The mechanisms of trastuzumab resistance are somewhat complex. The present work aims to explore the mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas. Methods: Firstly, the HER2 wild type (WT) and HER2 mutant (HER2 Q429R, HER2 Q429H and HER2 T798M are the commonest 3 types of mutations) MCF7 cell lines were established. Cell proliferation inhibition was then assessed by the Cell Counting Kit-8 assay and BrdU assay. Transwell invasion assays were also conducted to investigate the metastatic potential influenced by the HER2 mutation. Furthermore, Western blotting and co-immunoprecipitation were conducted to detect protein levels and the physical interaction of HER2 and trastuzumab. Results: The results showed that the mutant MCF7 cells were less sensitive to trastuzumab than the WTMCF7 cells. The mutation of HER2 almost had no influence on the expression of HER2 and the interaction of HER2 and trastuzumab. Finally, the mutation of HER2 weakened the inhibition of trastuzumab in the PI3K/AKT pathways. In addition, the inhibition of PI3K/AKT signaling-pathway increased the trastuzumab-sensitivity of HER2-mutant MCF7 cells. Conclusions: Dysregulation of the PI3K-AKT signaling-pathway was a key mechanism inducing the trastuzumab-resistance to HER2 mutant breast cancer cells.

Inflammatory breast cancer (IBC) is an infrequent but aggressive manifestation of breast cancer, which accounts for 2–4% of all breast cancer cases but responsible for 7–10% of breast cancer-related deaths, and with a 20–30% 10-year overall survival compared with 80% for patients with non-IBC with an unordinary phenotype, whose molecular mechanisms are still largely unknown to date. Discovering and identifying novel bio-markers responsible for diagnosis and therapeutic targets is a pressing need. MicroRNAs are a class of small non-coding RNAs that are capable to post-transcriptionally regulate gene expression of genes by targeting mRNAs, exerting vital and tremendous affects in numerous malignancy-related biological processes, including cell apoptosis, metabolism, proliferation and differentiation. In this study, we review present and high-quality evidences regarding the potential applications of inflammatory breast cancer associated microRNAs for diagnosis and prognosis of this lethal disease.

Cancer drug resistance poses a significant challenge in oncology, often driven by intricate cross-talk among membrane-bound receptors that compromise mono-targeted therapies. We develop a dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR/HER2 and (2) PD-L1/VISTA. Through modular optimization of modality configurations and geometries, we identify the “string” format as the most effective construct. Mechanistic studies demonstrate an ~85% increase in EGFR-binding affinity compared to the conventional knob-into-hole design, likely contributing to the improved efficiency of dual-target degradation. Proof-of-concept studies reveal that EGFR and HER2 FolTAC-dual effectively counteracts resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenates immune responses in PD-L1 antibody-resistant syngeneic mouse models. These findings establish FolTAC-dual as a promising dual-degradation platform for clinical translation.

Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer. Furthermore, we estimated the landscape of relationship between LAG3 and ten types of cell populations in breast cancer. Gene ontology analysis revealed LAG3 were strongly correlated with immune response and inflammatory activities. We investigated the correlation pattern between LAG3 and immune modulators in pan-cancer, especially the synergistic role of LAG3 with other immune checkpoints members in breast cancer. Conclusions LAG3 expression was closely related to malignancy of breast cancer and might serve as a potential biomarker; LAG3 might plays an important role in regulating tumor immune microenvironment, not only T cells, but also other immune cells. More importantly, LAG3 might synergize with CTLA4, PD1/ PDL1 and other immune checkpoints, thereby lending more evidences to combination cancer immunotherapy by targeting LAG3, PD1/PDL1, and CTLA4 together.