Fernanda Aparecida Marqueto1, Gabriela Fontana de Mesquita1, Rafaela Trevisan Scandiuzzi1, Carla de Moraes Salgado1, Beatriz Cassaniga Talassi1, Leisa Lopes Aguiar1, Maurício Luís Sforça2, Silvana Aprarecida Rocco2, Gustavo Henrique Rodrigues da Silva2, Guilherme de Moraes Nobrega3, Fernanda Garanhani de Castro Surita3, Maria Laura Costa do Nascimento3, Maria Cristina Cintra Gomes Marcondes1, Lais Rosa Viana1
Cancer during pregnancy is a rare condition, occurring in approximately 1 in every 1,000 pregnancies, with breast cancer being the most prevalent type. The incidence of pregnancy-associated breast cancer (PrBC) ranges from 1 in 3,000 to 10,000 women, and although it is rare, its incidence is increasing significantly due to advanced maternal age. Among the available treatment options in this context, chemotherapy is the most commonly used, being administered from the second trimester onwards. Both the tumor and chemotherapy act as stress factors for the placenta, leading to poor vascular perfusion, acute inflammatory lesions, delayed maturation of chorionic villi, metastatic lesions, reduced neovascularization, increased apoptosis, and genotoxic DNA damage, resulting in adverse fetal outcomes such as intrauterine growth restriction and preterm birth. Despite its high clinical relevance, little is known about the underlying mechanisms involved, especially at the omics level. Among omics approaches, metabolomics stands out as the one closest to the phenotype, providing valuable insights into alterations within the placental environment.
13 placentas were collected from patients who had breast cancer during pregnancy and underwent chemotherapy treatment (case group, N=6) and from healthy pregnant participants (control group, N=7). This study was approved by the ethics committee (CAAE: 65070122.0.0000.5404). Metabolites were extracted from the chorionic villi (CV) and analyzed by Nuclear Magnetic Resonance (NMR). Metabolites were identified and quantified using Chenomx software (Figure 1). Subsequently, multivariate statistical analyses were performed using MetaboAnalyst software, where adjusted P-values with FDR < 0.05 were considered significant.
A total of 53 metabolites were identified, of which 35 showed increased concentration in the case group compared to the control group. Principal Component Analysis (PCA) showed a clear separation in the metabolomic profile (PC1: 57% and PC2: 14.1%) (Figure 2A), with increased concentration in the case group relative to the control (Figure 2B). Enrichment analysis revealed 12 significantly altered metabolic pathways (Figure 2C). The metabolites involved in common pathways included L-asparagine, Histidine, L-arginine, Glutamine, Fumaric acid, L-alanine, Glycine, Pyruvic acid, L-aspartic acid, NAD, and Glutamic acid. On the other hand, metabolites involved in specific pathways were Citric acid and Lactic acid (Warburg effect), Uracil (beta-alanine metabolism), L-carnitine and Lysine (carnitine synthesis), Proline and Creatine (arginine and proline metabolism), Glycine, Methionine, and L-threonine (glycine and serine metabolism), and Glutathione (glutathione metabolism) (Figure 2C).
The identified pathways reveal significant metabolic adaptation of PrBC in this context. These changes may reflect protective remodeling to preserve placental function. Processes such as cell proliferation, amino acid metabolism, antioxidant defenses, and cellular signaling highlight the adaptive response of the placenta to maternal pathology and gestational demands. These findings strengthen the understanding of placental resilience in maternal and fetal health under challenging conditions.
Agradecimentos: FAPESP (#2023/09916-0; #2025/00592-2; 2017/02739-4; 2021/08931-0); CAISM - Hospital da Mulher Prof. Dr. José Aristodemo Pinotti (UNICAMP); CNPEM/LNBio - Centro Nacional de Pesquisa em Energia e Materiais.