Nuclear protein-1 (NUPR1) is also known as Com-1 or p8. It is a protein primarily found in the nucleus of various cells, including cancer cells, and it has been found to play an important role in cell stress and stress-related apoptosis. Over the past two decades, NUPR1 has been firmly indicated to play a role in the development and progression of numerous types of cancer, as well as in a number of other pathological conditions, including pancreatitis, diabetes, neurological and inflammatory conditions. The past decade has witnessed a rapid understanding of the biological and cellular mechanisms through which NUPR1 operates on cells and the identification of new variant of the protein. Most importantly, there have been comprehensive studies on the clinical and pathological aspects of NUPR1 and its variant in multiple malignancies and identification of therapeutic methods by targeting the protein.The present review aimed to summarise the current knowledge relating to NUPR1 in human malignancies and to discuss the associated controversies and potential future prospects of this molecule.

Activated leukocyte cell adhesion molecule (ALCAM), also known as CD166, is a cell adhesion protein that is found in multiple cell types. ALCAM has multiple and diverse roles in various physiological and pathological conditions, including inflammation and cancer. There has been compelling evidence of ALCAM’s prognostic value in solid cancers, indicating that it is a potential therapeutic target. The present article overviews the recent findings and progress in ALCAM and its involvement in cancer, with a primary focus on its clinical connections in cancer and therapeutic values.

Introduction. Endomucin-1 and endomucin-2 are two proteins structurally related, yet with low homology. The membrane bound sialoglycoproteins appear to play a key role in interfering with the formation of focal adhesion complexes (FAC) and matrix adhesiveness of cells, by mechanisms independent of the MUC1 repeat, which the endomucins do not possess. Endomucins are thought to be expressed at high levels in endothelium and haematopietic cell lineages, although the levels in mammary tissues also seem high. Despite the seeming importance of endomucins in the adhesion and migration of cells, including cancer cells, the clinical value of endomucin in clinical cancer, including breast cancer, is largely unknown. The present study examined the expression profile of endomucins, together with the focal adhesion kinase FAK, in breast cancer and aimed to explore the cellular impact of endomucin on cancer cells. Methods. Human breast cancer cells MCF-7 and MDA MB-231 and a range of other cell types were used. An endomucin overexpression cell model was created and subsequently used to evaluate the function of the cells. The expression profile of the endomucin-1 and endomucin-2 transcripts and FAK, in an existing fresh frozen breast cancer tissue cohort, were quantified. Results. High levels of endomucins, particularly endomucin-1, are good indicators for the overall survival of the patient, p=0.021 for endomucin-1 and p=0.15 for endomucin-2. When expression levels of FAK were integrated into the survival analysis model, patients with high levels of both endomucins and low levels of FAK had the most favourable outcome, compared with those with most unfavourable outcome who had low level of endomucin and high FAK (survival during the follow up period respectively at 100% and 54%, p=0.013, Harzoud Ratio 0.298). Together with the Nottingham Prognostic Index, which independently predicts a poor outcome (p=0.009, HR=7.6), the integrated expression profile of endomucin/FAK represents an independent prognostic indicator for favourable overall survival (p=0.003, HR=0.13), and indeed for a favourable disease free survival (p=0.008, HR=0.17). Mammary tissues, and indeed breast cancer cell lines, expressed high levels of endomucin-2 transcripts and low levels of endomucin-1 transcripts. High levels of endomucin-2 were also seen in fibroblasts and vascular endothelial cells. We created a breast cancer cell submodel with MCF-7, by overexpressing endomucin. It was shown that although endomucin over-expression had some marginal impact on the adhesiveness of breast cancer cells, the over-expression however, had significant impact on cells’ sensitivity to FAK inhibitor, with a markedly reduced adhesiveness to matrix (p< 0.001 control versus endomucin overexpression cells). Discussion. Endomucins have a reduced expression in breast cancers and the reduction, together with low levels of focal adhesion kinase, facilitate a favourable outcome for the patients. Together with the findings of in vitro cell models, it would suggest that the expression profile of endomucins and FAK may be a good indicator, not only for evaluating clinical outcomes, but also for choice of target therapies. Citation Format: Amber Xinyu Li, Tracey A. Martin, Lin Ye, Andrew J. Sanders, Fiona Ruge, Jane Lane, Eleri Davies, Wen G. Jiang. Endomucins and their expression in breast cancer and the cellular and therapeutic impact [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-17.

Introduction. The striatin protein family are calmodulin binding scaffolding proteins. Striatins have been involved in cell signalling and recently found also acting as cell adhesion molecules and adhesion regulators in adherens junctions and tight junctions. Straitins, particularly striatin-2 forms a recently discovered protein complex, STRIPAK, with other complex members including Protein Phosphatase-2 (PP2), STRIP, SIKE1 and certain PP2 regulatory proteins. The STRIPAK regulates multiple cell functions including gene transcription, endo- and exocytosis and cell adhesion, and several other important cell functions in cancer development and progression. The constitute members of the striatin protein complex may thus have important clinical bearings. In the present study, we investigated the expression profile of the striatin family members and key members of their interacting proteins, and discerned the relationship between the expression and disease progression and clinical outcome. Methods. Using an established fresh frozen breast cancer tissues cohort that included both normal mammary tissues and cancer tissues, we quantitatively evaluated the transcript expression of striatin-1 (STRN), striatin-3 (STRN3), straitin-4 (STRN4), its key regulator calmodulin (CALM) and the protein complex regulators protein phosphatase-2A (PPP2A), -2B (PPP2B) and the PPP2 regulatory elements PPP2R4 and PPP2R1A. The expression of each molecule was assessed against the clinical, pathological and prognostic factors of the patients. The integrated pattern of the complex members were also tested against the clinical outcome. Results. All three striatin members were expressed at good levels in mammary tissues and cancer tissues. STRN had little significant value against clinical and pathological factors. STRN3 and STRN4 were seen at high levels in tumours of high grade, with node positivity and with breast cancer related incidence. It was high level expressions of STRN3, STRN4 and CALM that were respectively associated with shorter overall survival (OS) of the patients and together they formed a poor prognostic indicator (p=0.034, HR=1.7). STRN had little impact on clinical outcomes. In a clear contrast, high levels of PPP2A, PPP2B and PPPR1A, but not PPP2R4, were seen in patients with significantly longer OS and together form a favourable prognostic indicator (p=0.034, HR=0.685). Integration of both STRN group and PPP2 group indicators constitutes a highly significant prognostic indicator for OS (p< 0.00001, HR=2.1 (95%CI 1.36-3.07)) and DFS (p=0.003, HR=1.402 (95%CI 1.12-1.75)). The predictive value of the integrated profile is independent of other clinical, pathological and hormone receptor status in multivariate analyses with OS (p< 0.0001, HR=3.861) and for DFS (p< 0.001, HR=2.055 (95%CI 1.36-3.07)). The same value stands when applied for the subtypes including triple negative breast cancers. Discussion. The STRIPAK complexes including Striatins play important regulatory roles in various cell functions and cancer development. Consistently, we found that high level expressions of STRN3, STRN4 and CALM, as a poor prognostic indicator were associated with shorter overall survival (OS) of the patients, while high levels of PPP2A, PPP2B and PPPR1A, as a favourable prognostic indicator, were seen in patients with significantly longer OS. Combination of both STRN group and PPP2 group indicators constitutes a greater significant prognostic indicator for OS and DFS. Future studies should focus on investigating the exact roles of the STRIPAK in cancer development and progression. Citation Format: Amber Xinyu Li, Andrew J. Sanders, Tracey A. Martin, Lin Ye, Fiona Ruge, QingPing Dou, Eleri Davies, Wen G. Jiang. Striatin and its interactive proteins Protein Phosphatase-2 (PP2) and PP2 regulatory elements in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-33.

Background. Activated Leukocyte Cell Adhesion Molecule, ALCAM (also known as CD166) is a member of the immunoglobulin superfamily and a cell surface adhesion molecule involved in heterophilic and homophilic interactions during cell-cell adhesion in epithelial cells, cancer cells and endothelial cells. ALCAM appears to be linked to tumour progression in a number of cancers including breast cancer, though there are conflicting reports as to its precise prognostic implications and significance. We have previously reported that ALCAM has a tumour suppressive role in breast cancer and is inversely correlated with clinical outcome (1) and interestingly bone metastasis of breast cancer (2). We have also reported that ALCAM has a diverse role in other cell types including keratinocytes and endothelial cells. In the present study, we investigated the association between ALCAM and hepatocyte growth factor (HGF)/cMET, a signalling pathway established as a key promoter of cancer progression, influencing both the aggressive nature of cancer cells and acting as an angiogenic and lymphangiogenic factor, in breast cancer and endothelial cells. Methods. The expression pattern and correlation of ALCAM, HGF and cMET in human breast cancer were deduced from a clinical breast cancer cohort. ALCAM manipulated HECV cell lines, previously established in our laboratories, were used in conjunction with recombinant human HGF and cMET inhibitors to assess cellular functions and the implications of this relationship at a cellular level. Results. We compared the expression of ALCAM with that of HGF and cMET within the breast cancer cohort and found that ALCAM/CD166 showed a highly significant negative correlation with the HGF receptor cMET (r=-0.17, p<0.0001) and a weak negative correlation with HGF, although this was not significant. ALCAM was not found to correlate with its heterophilic partner CD6. In previously generated HECV models, ALCAM manipulation showed a marked influence on cellular function and responsiveness to HGF treatment. Discussion. ALCAM’s role in breast cancer progression and related mechanisms is complex. Our current data suggests this may involve an interaction with the cMET/HGF signalling pathway and may also impact the endothelial component within the tumour microenvironment to influence disease progression. Reference1 King JA, Ofori-Acquah SF, Stevens T, et al. Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator. Breast Cancer Res. 2004;6:R478-87. Reference2 Davies SR, Dent C, Watkins G et al. Expression of the cell to cell adhesion molecule, ALCAM, in breast cancer patients and the potential link with skeletal metastasis. Oncol Rep. 2008;19:555-61. Citation Format: Andrew James Sanders, David Guo Jiang, Jianyuan Zeng, Robert Edward Mansel, Eleri Davies, Amber Xinyu Li, Keith Gordon Harding, Wen Guo Jiang. Potential role of activated leukocyte cell adhesion molecule (ALCAM) in hepatocyte growth factor (HGF) signalling in vascular endothelial cells and implications in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-48.