The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-19, pub-electronic 2021-10-22Publication status: PublishedFunder: Instituto de Salud Carlos III; Grant(s): PI18/00442Funder: European Commission; Grant(s): ITN-308 2016 721532Funder: Breast Cancer Now; Grant(s): 2012NovSP033Funder: Ministry of Economy, Industry and Competitiveness; Grant(s): RTI2018-094130-B-100Background: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. Methods: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinformatic analyses in public datasets. Results: TRIB3 enhanced the proliferation and AKT phosphorylation in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. Conclusions: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer

Papel de la proteína Ambra 1 en el desarrollo y progresión de carcinomas de células escamosas

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 02/06/2023Squamous cell carcinomas (SCC), also known as epidermoid carcinomas, comprise several different types of cancers that emerge from squamous cells. Cutaneous squamous cell carcinoma (cSCC) arising from malignant epidermal keratinocytes, is the second most frequent skin cancer in humans after basal cell carcinoma (BCC). This figure continues to rise and is underestimated. UV radiation is the main risk factor that generates a burden of mutations that trigger the development of cSCC. While it usually exhibits benign clinical behaviour, it can be locally invasive and metastatic. Ten-year survival after surgery exceeds 90% for cSCC but drops dramatically when metastases occur. Given its high frequency, cSCC has a significant impact on overall mortality. So, the identification of prognostic biomarkers would help identify the most aggressive tumours.The AMBRA1 protein, highly conserved among vertebrates, was discovered in 2007. Regarding protein structure, the intrinsic disorder accounts for the great plasticity, making AMBRA1 an excellent scaffold-molecular candidate able to interact with several proteins and thus, regulate a plethora of biological processes. In cancer, AMBRA1 has been identified as a tumour suppressor gene in the context of different types of neoplasms due to its ability to regulate proliferation and invasiveness...Los carcinomas de células escamosas (SCC), también conocidos como carcinomas epidermoides, comprenden varios tipos de tumores que surgen de las células escamosas. El carcinoma cutáneo de células escamosas (cSCC), que deriva de queratinocitos malignos localizados en la epidermis, es el segundo cáncer de piel más frecuente en humanos después del carcinoma de células basales. Esta cifra sigue aumentando y está infravalorada. La radiación UV es el principal factor de riesgo que genera una carga de mutaciones que desencadena el desarrollo del cSCC. Aunque suele presentar un comportamiento clínico benigno, puede ser localmente invasivo y metastásico. La supervivencia a diez años tras la cirugía supera el 90% en el caso del cSCC, pero desciende drásticamente en caso de metástasis. Dada su elevada frecuencia, el cSCC tiene un impacto significativo en la mortalidad global. Por ello, la identificación de biomarcadores de pronóstico ayudaría a identificar los tumores más agresivos. La proteína AMBRA1, conservada entre los vertebrados, fue descubierta en 2007. En cuanto a la estructura de la proteína, el desorden intrínseco explica su gran plasticidad, lo que convierte a AMBRA1 en un excelente andamio molecular capaz de interactuar con varias proteínas y, por tanto, de regular una amplia variedad de procesos biológicos. En el contexto del cáncer, AMBRA1 ha sido identificado como un gen supresor tumoral en diferentes tipos de neoplasias debido a su capacidad para regular la proliferación y la invasión...Fac. de Ciencias BiológicasTRUEunpu

The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

Background: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. Methods: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinformatic analyses in public datasets. Results: TRIB3 enhanced the proliferation and AKT phosphorylation in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. Conclusions: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer