The Profile of Expression of SG2NAs Differs Between Cancer Types and it is Involved in the Reprogramming of Tumour Cell Proteome.

Striatin and SG2NA are scaffold proteins that from signalling complexes called STRIPAK. It has been associated with cancer and other diseases. Our earlier studies have shown that SG2NA forms a complex with the cancer associate protein DJ-1 and signalling kinase Akt, promoting cancer cell survival. In the present study, we used bioinformatics analyses to confirm the existence of two isoforms of human SG2NA i.e., 78 and 87 kDas. In addition, several smaller isoforms like 35 kDa were also seen in western blot analyses of human cell lysates. The expression of these isoforms varies between different human cancer cell lines. Also, the protein level does not corroborate with its transcript level, suggesting a complex regulation of its expression. In breast tumour tissues, the expression of the 35 and 78 kDa isoforms was higher as compared to the adjacent normal tissues, while the 87 kDa isoform was detected in the breast tumour tissues only. With the progression of stages of breast cancer, the expression of 78 kDa isoform decreased, while 87 kDa became undetectable. In coimmunoprecipitation assay, the profile of SG2NA interactome in breast tumor vis-à-vis adjacent normal breast tissues shows hundreds of common proteins, while some proteins specifically interacted in breast tumour tissue only. We conclude that SG2NA is involve in diverse cellular pathways and have roles in cellular reprogramming during tumorigenesis.

Sodium accumulation in breast cancer predicts malignancy and treatment response

Breast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive 23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+ concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models. Ex vivo SBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by 1H diffusion-weighted imaging (DWI). Moreover, combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using 23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.

Binary and ternary crystal structure analyses of a novel inhibitor with 17β-HSD type 1: a lead compound for breast cancer therapy

Oestradiol is a well-characterized sex hormone that stimulates breast cancer and other oestrogen-related diseases. 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step in the synthesis of oestradiol and androstenediol in breast tumour tissue. The enzyme's high expression and activity after simultaneous blockade of oestrogen receptors and inhibition of aromatase in the tumour shows the necessity for its inhibition as a requirement for breast cancer therapy. In the present paper, we report structures of the binary and ternary complexes of 17β-HSD1 with a new inhibitor E2B {3-[3′,17′β-dihydroxyestra-1′,3′,5′(10′)-trien-16′β-methyl]benzamide}, and the enzyme inhibition by the later. The IC50 value for E2B was determined to be 42 nM in T47D cells. Multiple interactions between E2B and the enzyme include hydrogen bonds and hydrophobic interactions, as well as π–π interactions. A kinetic study demonstrated that E2B inhibits the enzyme's reduction forming oestradiol from oestrone, with a Ki of 0.9±0.15 nM. Such strong inhibition is in agreement with its extensive interaction with the enzyme, suggesting its potential as a lead compound for breast cancer therapy. In fact, this possibility is enhanced by its capacity for cell penetration similar to natural steroids. Such inhibitors that block oestrogen synthesis to suppress the sulfatase pathway producing oestradiol can be used in adjuvant therapies with oestrogen receptor blockade, opening a new orientation of breast cancer treatment.