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.
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 PubMed 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 PubMed PMID: 26359358.
Avtanski DB, Nagalingam A, Kuppusamy P, Bonner MY, Arbiser JL, Saxena NK, Sharma D. Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-β-catenin signaling axis in a microRNA-34a dependent manner. Oncotarget. 2015 PubMed PMID: 26036628.
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 PubMed PMID: 24732433.
Saxena NK, Sharma D. Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia. 2013 PMID: 24214584.