Abstract
Total choline (tCho) was documented as a biomarker for breast cancer diagnosis by in vivo MRS. To understand the molecular mechanisms behind elevated tCho in breast cancer, an association of tCho with β-catenin and cyclin D1 was evaluated. Hundred fractions from 20 malignant, 10 benign and 20 non-involved breast tissues were isolated. Cytosolic and nuclear expressions of β-catenin and cyclin D1 were estimated using ELISA. Higher tCho was seen in malignant compared to benign tissues. Malignant tissues showed higher cytosolic and nuclear β-catenin expressions than benign and non-involved tissues. Within malignant tissues, β-catenin and cyclin D1 expressions were higher in the nucleus than cytosol. Cyclin D1 expression was higher in the cytosolic fractions of benign and non-involved than malignant tissues. Furthermore, in malignant tissues, tCho showed a positive correlation with the cytosolic and nuclear expression of β-catenin and cyclin D1 and also a correlation between nuclear expressions of both these proteins was seen. Higher cytosolic β-catenin expression was seen in progesterone receptor negative than positive patients. Results provide an evidence of correlation between non-invasive biomarker, tCho and the Wnt/β-catenin pathway. The findings explain the molecular mechanism of tCho elevation which may facilitate exploration of additional therapeutic targets for breast cancer.
Highlights
Breast cancer ranks second as a cause of cancer death in women and is a substantial cause of mortality and morbidity among women worldwide[1]
The expression of cyclin D1 was studied in the same set of samples and it was found to be significantly overexpressed in nuclear fraction [2.1 (2.0–2.7) ng/ml] when compared to the cytosolic fraction [2.0 (1.0–2.3) ng/ml]
A significantly higher expression of cyclin D1 in the nuclear fraction of malignant tissues was seen in comparison with benign and non-involved breast tissues (Fig. 3d, Table 1)
Summary
Breast cancer ranks second as a cause of cancer death in women (after lung cancer) and is a substantial cause of mortality and morbidity among women worldwide[1]. A disruption of these pathways results in an altered cell-cell and cell-extracellular matrix interaction that eventually leads to uncontrolled cellular proliferation and development of a tumor[3] Both estrogen and progesterone are examples of two such steroid hormones which are involved in the regulation of mammary gland development, but are found to be associated with the initiation, development, and progression of breast cancer[3]. A multiprotein destruction complex is formed with the phosphorylation of β-catenin (at Serines 33, 37, and Threonine 41) by dishevelled protein (Dvl) and binding of Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase 3 β (GSK 3β) This is followed by poly-ubiquitination and subsequent degradation of β-catenin by the ubiquitin-proteasome mediated pathway. The implication of cyclin D1 in various malignancies, including breast cancer[13, 14] emphasizes the importance of studying this protein in malignant transformation and cancer progression
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