Ana Carolina Pavanelli1,2, Flavia Rotea Mangone1,2, Piriya Yoganathan3, Simone Aparecida Bessa1,2, Suely Nonogaki4, Cynthia A B de Toledo Osório4, Victor Piana de Andrade4, Iberê Cauduro Soares5, Evandro Sobrosa de Mello5, Lois M Mulligan3, Maria Aparecida Nagai6,7. 1. Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, 01246-903, Brazil. 2. Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of Sao Paulo, São Paulo, 01246-000, Brazil. 3. Department of Pathology and Molecular Medicine, Cancer Research Institute, Queen's University Kingston, 18 Stuart Street, Kingston, ON, K7L 3N6, Canada. 4. Department of Pathological Anatomy, A. C. Camargo Cancer Center, São Paulo, 01509-020, Brazil. 5. Department of Pathology, Cancer Institute of Sao Paulo, Hospital das Clinicas, Faculty of Medicine, University of São Paulo, HCFMUSP, São Paulo, 01246-903, Brazil. 6. Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, 01246-903, Brazil. nagai@usp.br. 7. Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of Sao Paulo, São Paulo, 01246-000, Brazil. nagai@usp.br.
Abstract
PURPOSE: Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. METHODS: Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. RESULTS: Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). CONCLUSION: Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.
PURPOSE: Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. METHODS: Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. RESULTS: Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). CONCLUSION: Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.
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