My research work focuses on various aspects of breast carcinogenesis, particularly the molecular and hormonal mechanisms underlying breast tumor growth, epithelial-mesenchymal transition, invasion, migration and breast cancer prevention. My studies have established important markers for development of acquired tamoxifen resistance. We found that higher expression levels of Mediator-1 in the breast tumors significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. I have also made important contributions to the field of obesity-cancer connection and have established important links between adipocytokines and cancer progression; this understanding has had a major translational impact. To understand the molecular mechanisms involved in breast cancer progression, we are exploring genes, molecules, hormones and cellular processes that could cause and promote cancer. I am also studying the role and importance of adipocytokines and bioactive food components in breast carcinogenesis for the last several years. Innovation in our research is demonstrated by seminal discoveries in adipocytokines and bioactive compound research. For example, we were first to demonstrate that leptin promotes epithelial-mesenchymal transition in breast cancer cells. Studies from our lab have shown various oncogenic effects of adipokine-leptin and elucidated the underlying molecular mechanims. We have shown that leptin promotes proliferation as well as metastatic potential of breast carcinoma specifically augmenting the invasion and migration potential. Our studies showed the involvement of multiple signaling pathways in leptin function. Using various in vitro assays, in vivo mouse models (chemically-induced, transgenic, xenograft, diet-induced obesity models) and analysis of human breast cancer samples and correlation with clinicopathological data, we have shown the importance of leptin in breast tumor progression. We are actively investigating novel molecular targets and pathways involved in chemopreventive role of bioactive components. We are examining the alterations in microbiome and how microbial dysbiosis and metabolomics changes fuel cancer progression.
Sengupta S, Nagalingam A, Muniraj N, Bonner MY, Mistriotis P, Afthinos A, Kuppusamy P, Lanoue D, Cho S, Korangath P, Shriver M, Begum A, Merino VF, Huang CY, Arbiser JL, Matsui W, Győrffy B, Konstantopoulos K, Sukumar S, Marignani PA, Saxena NK, Sharma D. Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene. 2017 PMID: 28581518.
Chung SJ, Nagaraju GP, Nagalingam A, Muniraj N, Kuppusamy P, Walker A, Woo J, Győrffy B, Gabrielson E, Saxena NK, Sharma D. ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis. Autophagy. 2017 PMID: 28696138.
Avtanski DB, Nagalingam A, Tomaszewski JE, Risbood P, Difillippantonio MJ, Saxena NK, Malhotra SV, Sharma D. Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis. Mol Oncol. 2016 PMID: 27259808.
Avtanski DB, Nagalingam A, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer. Oncotarget. 2015 PMID: 26359358.
Nagalingam A, Kuppusamy P, Singh SV, Sharma D, Saxena NK. Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer. Cancer Res. 2014 PMID: 24732433.