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Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Breast cancer is one of the leading causes of cancer death in women, and although treatment outcome has substantially improved in the past decades, advanced or metastatic breast cancers still carry a poor prognosis. Gene amplification is one of the frequent genetic alterations in cancer, and oncogene amplification may be associated with cancer aggressiveness and oncogenicity. Targeting amplified genes such as HER2 has vastly improved disease outcome and survival, and anti-HER2 therapeutics have revolutionized the standard of care in HER2 breast cancer. Besides currently known druggable gene amplifications including ERBB2 and FGFR2, other frequently amplified genes are relatively less well known for function and clinical significance. By querying 4 large databases from TCGA and AACR-Genie, from a total of 11,890 patients with invasive ductal breast carcinoma, we discover IKZF3, CCND1, ERBB2 to be consistently amplified across different cohorts. We further identify IKZF3 as a frequently amplified gene in breast cancer with a prevalence of 12–15% amplification rate. Interestingly, IKZF3 amplification is frequently co-amplified with ERBB2/HER2, and is also associated with worse prognosis compared to IKZF3 non-amplified cancers. Analysis of HER2 breast cancer patients treated with trastuzumab revealed decrease in both ERBB2/HER2 and IKZF3 expression. Further investigation using the DepMap for gene dependency by genome wide CRISPR screening revealed dependence on IKZF3 in HER2 breast cancer cell lines. Our study utilized an integrative analysis of large scale patient genomics, transcriptomics and clinical data to reveal IKZF3 as a frequently amplified gene, and suggest a potential role of IKZF3 as a druggable target for HER2 breast cancer.

For the application of In-49Sn solder in bonding recycled-sputtering targets to Cu back plates, the intermetallic compounds formed at the In-49Sn/Cu interface are investigated. Scanning electron microscopy (SEM) observations show that the interfacial intermetallics consist of a planar layer preceded by an elongated scalloped structure. Electron-probe microanalyzer analyses indicate that the chemical compositions of the planar layer and the scalloped structure are Cu74.8In12.2Sn13.0 and Cu56.2In20.1Sn23.7, respectively, which correspond to the ɛ-Cu3(In,Sn) and η-Cu6(In,Sn)5 phases. Kinetics analyses show that the growth of both intermetallic compounds is diffusion controlled. The activation energies for the growth of η- and ɛ-intermetallics are calculated to be 28.9 kJ/mol and 186.1 kJ/mol. Furthermore, the formation mechanism of intermetallic compounds during the In-49Sn/Cu soldering reaction is clarified by marking the original interface with a Ta-thin film. Wetting tests are also performed, which reveal that the contact angles of liquid In-49Sn drops on Cu substrates decline to an equilibrium value of 25°C.

The interfacial reactions between liquid In and Cu substrates at temperatures ranging from 175°C to 400°C are investigated for the applications in bonding recycled sputtering targets to their backing plates. Experimental results show that a scallop-shaped Cu16In9 intermetallic compound is found at the Cu/In interface after solder reactions at temperatures above 300°C. A double-layer structure of intermetaltic compounds containing scallop-shaped Cu11In9 and continuous CuIn is observed after the Cu/In interfacial reaction at temperatures below 300°C. The growth of all these intermetallic compounds follows the parabolic law, which implies that the growth is diffusion-controlled. The activation energies for the growth of Cu16In9, Cu11In9, and CuIn intermetallic compounds calculated from the Arrhenius plot of growth reaction constants are 59.5, 16.9, and 23.5 kJ/mole, respectively.