The potential role of the hedgehog signalling pathway in the regulation of epithelial-mesenchymal transition in breast cancer

Breast cancer is a deadly disease that accounts for a third of all female cancer- related deaths globally. Although recent advances in early diagnosis and targeted therapy using prognostic markers have reduced deaths, more than 50% of newly diagnosed cases have already developed metastatic disease at diagnosis. Furthermore, the remaining cases still have a high risk of secondary disease and relapse. Breast cancer metastasis is the leading cause of breast cancer related mortality, it is incurable and current treatments aims to prolong life alongside pain management. Thus, there is a need for treatment for this disease.The epithelial-mesenchymal transition (EMT) is the process by which cancer cells acquire the ability to invade and eventually metastasise. Therefore, understanding the regulation of breast cancer cell metastasis is essential for identifying methods for management of metastatic disease either by prevention or treatment. The first aim of this study was to confirm the ability of breast cancer cell lines, that belong to several molecular subtypes to undergo EMT using an in vitro seeding density model. Results showed that there was active EMT in breast cancer cell lines and that the activation of these pathways is not restricted to, nor governed by, molecular subtypes of breast cancer. Then to identify pathways involved in regulating EMT and utilising these pathways as prognostic marker as well as for developing treatments.The Hedgehog (Hh) signalling pathway is involved in the regulation of EMT during mammary gland development stages. This pathway was involved in the progression and metastasis of many human cancers. So, the expression of a number of proteins involved in the Hh pathway were assessed in a cohort of breast cancer patient samples. The expression of these proteins in the tumour centre and also the invasive front was assessed and correlated with the clinicopathological criteria. Data from breast cancer cohort showed that there was increased expression of Hh proteins (Gli1, Gli2 and Gli3) at the invasive front. Also, the data suggested that breast cancer cells gain the ability to activate Hh signalling by autocrine rather than by paracrine signalling. These findings encouraged further investigation to understand the effect of inhibiting the Hh signalling using cyclopamine or LDE225 in vitro.Inhibition with cyclopamine or LDE225 resulted in a reduction of cell yield and viability that correlated with increased cellular apoptosis. The reduction in viability and increased cell death was associated with alteration of Hh proteins expression and subcellular localisation. Also, assessment of the catenin-related transcription, that measured the outputs of canonical Wnt signalling, showed that inhibiting Hh signalling using cyclopamine and LDE225 resulted in reduction of Wnt signalling activity in both cell lines. Assessment of E-cadherin expression showed that Hh inhibition caused increased of expression in both cell lines, that was associated with a reduction of cells invasion.Findings showed that Hh signalling was involved in the regulation of EMT and that there was crosstalk between Hh and Wnt signalling in breast cancer cells. It can be concluded that the combined activation of Hh and Wnt signalling in breast cancer was associated with increased metastasis as a result of EMT activation. Assessment of the co-expression of Hh and Wnt signalling proteins in breast cancer samples provides potential prognostic markers for identifying breast cancer patients who that could benefit from Hh-targeted therapy

Hypoxia modulates the stem cell population and induces EMT in the MCF-10A breast epithelial cell line

A common feature among pre-malignant lesions is the induction of hypoxia through increased cell propagation and reduced access to blood flow. Hypoxia in breast cancer has been associated with poor patient prognosis, resistance to chemotherapy and increased metastasis. Although hypoxia has been correlated with factors associated with the latter stages of cancer progression, it is not well documented how hypoxia influences cells in the earliest stages of transformation. Using the immortalized MCF-10A breast epithelial cell line, we used hypoxic culture conditions to mimic reduced O2 levels found within early pre-malignant lesions and assessed various cellular parameters. In this non-transformed mammary cell line, O2 deprivation led to some changes not immediately associated with cancer progression, such as decreased proliferation, cell cycle arrest and increased apoptosis. In contrast, hypoxia did induce other changes more consistent with an increased metastatic potential. A rise in the CD44+CD24-/low-labeled cell sub-population along with increased colony forming capability indicated an expanded stem cell population. Hypoxia also induced cellular and molecular changes consistent with an epithelial-to-mesenchymal transition (EMT). Furthermore, these cells now exhibited increased migratory and invasive abilities. These results underscore the contribution of the hypoxic tumour microenvironment in cancer progression and dissemination

The potential role of hedgehog signaling in the luminal/basal phenotype of breast epithelia and in breast cancer invasion and metastasis

© 2015 by the authors; licensee MDPI, Basel, Switzerland. The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT

Differential expression of the BCAT isoforms between breast cancer subtypes

© 2020, The Author(s). Background: Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated. Methods: Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined. Results: We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression. Conclusion: The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism

The Association between Colorectal Cancer and Colonoscopic Conditions in Saudi Patients: A 10-Year Cross-Sectional-Retrospective Study

BACKGROUND: In Saudi Arabia, colorectal cancer (CRC) is the most common cancer in males and the third most common cancer in females. The current gold standard for colorectal cancer diagnosis is colonoscopy. Several concerns regarding the balance of ordering colonoscopy procedures for patients presenting with signs and symptoms. There are also several concerns regarding over-ordering the procedure when unnecessary. The current study aimed to evaluate the association between colorectal cancer and colonoscopic conditions in Saudi patients. METHODS: A 10-year cross-sectional study was conducted at Alnoor Specialty Hospital, Makkah, over the last ten years. Colonoscopy reports of patients were evaluated to identify the colonoscopy manifestations associated with mass, polyps, and bleeding. RESULTS: The current study evaluated 2158 cases admitted to the hospital for colonoscopic diagnosis. Results indicated that most of the patients were males (55.4%). Additionally, results showed a significant statistical association between tumor and bleeding, polyp, and hemorrhage. Moreover, it highlighted the association between polyps and bleeding, inflammation, and diverticulosis. CONCLUSION: CRC screening in Saudi Arabia is comprehensive; however, there are a few areas for improvement, including standardization of colorectal cancer pathology reporting to improve the health system's quality. Also, the current study identified conditions that are significantly associated with reported colon polyps and tumors, which could aid in stratifying patients selected for screening via colonoscopy

Patterns of Thyroid Cancer Mortality and Incidence in Saudi Arabia: A 30-Year Study

Thyroid cancer is the most prevalent endocrine cancer among the female population in the Kingdom of Saudi Arabia (KSA) and the ninth most common in the male population in Saudi Arabia. Over the past years, an increasing incidence of thyroid cancer has been reported in Saudi Arabia. However, the etiology of thyroid cancer is still not clear. Therefore, this study aimed to estimate thyroid cancer incidence and mortality trends in Saudi Arabia from 1990 to 2019. The current study utilized the Global Burden of Disease and the Institute for Health Metrics and Evaluation databases to extract prevalence data of thyroid cancer in Saudi Arabia from 1990 to 2019. Moreover, the current project utilizes Global Burden of Disease (GBD) web-based tools to visualize these data. In total, 23,846 cases (17,220 females and 6626 males) were diagnosed with thyroid cancer in Saudi Arabia from 1990 to 2019. The incidence is higher in females than in males. Over these 30 years, women’s incidence steadily increased by 15-fold versus a 22-fold increase in men. Moreover, there were 2056 deaths in total caused by thyroid cancer in KSA. The mortality rate in women steadily increased by threefold in the same period. However, the increase in mortality was higher in males (sixfold). A high percentage of YLLs was observed in males, with around 24.8% ranging from 30 to 34 and 40 to 45 years. Thyroid cancer incidence rates have increased exponentially between 1990 and 2019. The expansion of the incidence of thyroid cancer in Saudi Arabia could be due to the increased development in detection and diagnosis. The current study provided evidence of the need to increase awareness and diagnosis in the male population