Executive Summary : | Breast cancer (BC) is one the most frequently diagnosed cancer during pregnancy. Several aspects of pregnancy associated BC, including risk factors, biological events involved in its occurrence and aggressiveness and early diagnosis of women at risk of developing pregnancy associated BC are incompletely understood. Placental secretions during pregnancy are known to affect several physiological processes in the mother including mammary gland development to prepare for lactation. Few preclinical ex-vivo studies have indicated that, the placental tissue explants can trigger progression of BC cells pointing towards the possible influence of placental tissue derived factors in breast tumorigenesis during pregnancy. Wnt signaling is one of the most frequently altered pathways in BC as well as in premalignant breast tumors indicating that deregulations Wnt signal network could be an early event in pathogenesis of BC. Also, downregulation of Wnt pathway elements in breast epithelial cells has been shown to occur post pregnancy and suggested to be one of the mechanisms contributing to protective effect of early pregnancy against BC. However, not much is known regarding the involvement of Wnt pathway components in facilitating placenta regulated pathogenesis of BC during pregnancy Objectives: The study aims to understand the involvement of Wnt signal network in mediating placental tissue regulated process of breast carcinogenesis during pregnancy Hypothesis: The hypothesis tested in the present study is whether the placental-breast cross-talk is influenced by Wnt signaling pathway/its target genes and identify key pathways that effect breast carcinogenesis during pregnancy Methodology: To study effects of placental secretions on breast epithelial and BC cells, explants of placental tissue/chorionic villi will be co-cultured with breast cancer cell lines, on-malignant breast tumor cells, and normal breast epithelial cells (BE/BT/BC cells) followed by analysis of expression of Wnt pathway genes by qPCR/IF/Western Blot analysis. To study effect of blockade/activation of Wnt pathway on placenta mediated regulation of breast carcinogenesis, the BE/BT/BC cells exposed to placental tissue explants/placental cell supernatants will be treated with Wnt agonists/antagonist. And then used to study its subsequent effect on proliferation, adhesion, invasion, /stem cell renewal abilities of BE/BT/BC cells. Transcriptome analysis will be carried out by RNAseq to identify the placenta driven molecular signatures in BE/BT/BC cells in response to Wnt agonists/antagonists’ treatment. The candidate Wnt pathway genes associated with regulating placenta mediated changes in BE/BT/BC cells, will be further analyzed in tumor samples of PABC and non-PABC patients Significance: The present study would help determine the therapeutic efficacy of targeting Wnt signaling network regulated pathways in arresting the pathogenesis of pregnancy associated BC |
Co-PI: | Dr. Geetanjali Sachdeva, ICMR-National Institute For Research In Reproductive Health And Child Health, Mumbai, Maharashtra-400012, Dr. Jyoti Bajpai, Tata Memorial Centre (Hospital), Mumbai, Maharashtra-400012 |