Humanin promotes tumor progression in experimental triple negative breast cancer

Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer.Fil: Moreno Ayala, Mariela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Zuccato, Camila Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Pidre, Matias Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Imsen, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Romanowski, Victor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Creton, Aldo. Hospital Italiano de La Plata; ArgentinaFil: Isla Larrain, Marina Teresita. Hospital Italiano de La Plata; ArgentinaFil: Seilicovich, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentin

Counterbalance of Foxp3 and IDO expression at different tumor stages in aggressive breast cancer subtypes

Foxp3 and IDO1 are known immunomodulatory molecules involved in tumor escape and could be related to tumor infiltrating lymphocytes (TILs) in the tumor microenvironment. In this study, tumoral Foxp3 and IDO1 expression in breast cancer were evaluated in relation to lymphocyte biomarkers such as CD8 and CD45R0, regulatory T cells, as well as intratumoral and stromal TILs (iTILs and sTILs, respectively). Clinical and histopathological features were also included in the analysis. Foxp3 and IDO1 were found in tumor cells showing mainly cytoplasmic patterns in 60% and 62% tumor samples, respectively. TILs were found in 76% of samples; iTILs were detected in 92% of those samples and sTILs in 55%. Foxp3+ TILs were detected only in 12% of TILs+ samples associated with tumoral Foxp3 expression. Tumoral Foxp3 was mainly expressed at lower tumor stages while IDO1 expression was associated with advanced tumor stages; both correlated with CD8+ TILs which were observed in 77% of TILs+ samples. CD45R0+ were observed in 81% of TILs+ samples and correlated with higher tumor stages and poorly differentiated tumors. In ER negative tumors, an inverse correlation between Foxp3 and IDO1 tumoral expression was found in relation to tumor stage. TNBC subtype showed a positive correlation with the presence of iTILs. In silico analysis showed that Foxp3 and coexpressed genes in breast cancer were associated with immune response genes. Foxp3 was found predominantly in Basal and Her2-enriched subtypes in relation to Luminal A subtype, by RNA seq and RNA microarray database analysis. In conclusion, the expression of Foxp3 and IDO1 in tumors at different stages suggests a potential compensatory mechanism to evade the strong CTL response observed. This is relevant since the cumulative data indicates that Foxp3 as well as IDO1 could be potential targets of immunotherapy in patients with tumors at different stages and for the most aggressive breast cancer subtypes such as TNBC and Her2-enriched.Centro de Investigaciones Inmunológicas Básicas y Aplicada