This project involves the analysis of signal transducers in progression of breast cancer. As breast cancer is one of the most common cancers seen in women, silencing STATs may provide an effective therapeutic modality. Signal Transducers and Activators of Transcription (STAT) proteins are a family of latent cytoplasmic transcription factors involved in cytokine, hormone and growth factor transduction. STAT proteins are found to play an important role in controlling fundamental cellular processes of survival, proliferation and differentiation and mediating diverse biological processes such as cell growth, fetal development, inflammation and immune response. Aberrant activation of STATs is thought to contribute to transformation. Compelling evidence has accumulated revealing a critical role of STAT proteins in carcinogenesis. The up regulation of STATs, especially STAT3, has been clearly demonstrated in breast cancer, which could be due to cytokine induction. My work basically deals with studying the effect of IL-6 induced STAT3 gene expression in breast cancer. In addition to this, a major challenge to be addressed here is the selective inhibition of STAT3 and its regulated genes related to tumor growth and survival. This work aims to employ siRNA (small interfering RNA) or RNA interference (RNAi) technology, one of the most important discoveries in molecular oncology, to selectively silence the STAT gene with higher specificity and efficacy.

Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. CML is characterized by the Philadelphia (Ph) chromosome, which results from the t(9;22)(q34;q11) balanced reciprocal translocation. The molecular consequence of this translocation is the generation of the BCR-ABL1 oncogene that encodes the chimeric BCR-ABL1 protein with tyrosine kinase activity. The best known drug which is an inhibitor of the Bcr-Abl oncoprotein is Imatinib mesylate (IM), which has shown significant treatment responses, especially when applied during the early phases of CML. However, the cancer cells are evolving resistance to the drug, mainly through point mutations. Therefore, monotherapy with IM may not be the best option in CML. Addition of alternate TKIs which synergize with IM may enhance the effect of the targeted therapy. . This study aims at the synergistic anti-CML activity of IM with Indirubin, a Chinese anti-leukemia medicine, on IM-resistant and IM- sensitive conditions. The major expected outcome is the efficient reversal of imatinib resistance and effective cell killing via apoptosis. Nilotinib will be used as a positive control. This study may help identifying the exact molecular pathology behind imatinib resistance and help identifying new molecules to rectify the same. Moreover, the study may reveal new therapeutic approaches to halt imatinib resistance.

Colorectal cancer is the third most common form of cancer and the third leading cause of cancer-related death in the Western world. It is expected to cause about 49,380 deaths during 2011. The incidence and mortality rate of colorectal cancer is growing at an alarming rate in the Indian population too. Conventional chemotherapy in colorectal cancer is not as effective as it is in other cancers, as the drug does not reach the target site in its effective concentrations. Thus effective treatment demands increased dose size to compensate drug loss during passage through the upper gastrointestinal tract, which may lead to undue side effects. In order to improve this situation, there is a need to develop a colon-targeted delivery system that can deliver the drug more efficiently to the colon, where it can target the tumor tissues more specifically. I work on a collaborative DBT project titled “A novel site specifically targeting nanoparticle based oral - drug and siRNA releasing polymer systems for colon cancer”. The main objective of my work is to evaluate both drug and siRNA entrapped polymeric nanoparticle delivery system in colon cancer cell lines. The major limitation for the use of siRNA is the inability of naked siRNA to passively diffuse through cellular membranes. If the siRNA and the drug together can be entrapped in a biodegradable nanoparticle, conjugated with suitable targeting moiety, it will enhance the delivery of the drug as well as siRNA effectively in colon. The pH sensitive coating ensures its rupture in the colon and hence it’s slow release and safe therapy for colorectal cancer.

Cyclins and cyclin dependent kinases (cdks) regulate the cell division cycle in mammalian cells. The cyclin-cdk complex phosphorylates various cell cycle regulatory proteins which help in the progression of cells from one phase to another. On the other hand, cyclin dependant kinase inhibitors (CKIs) regulate various check points associated with cell division cycle. cks1 (cyclin dependent kinase subunit1) is one of the essential components of the cdks and has been found to be over-expressed in different human tumors. However, the exact role of its over-expression in cancers is still unclear. In addition to its role as an essential component of cyclin-cdk complexes, cks1 has also been known to function as an accessory protein of the SCF^Skp2 ubiquitinating machinery. Several studies in lower eukaryotes suggest cks1 to be essential for the cells during mitotic entry, progression and exit. Its close association with cdk1 has prompted us to investigate its role on cdk1 activation, a critical event during mitotic entry, progression and exit. Expression analysis of both cks1 and phospho-cdk1 was conducted in oral cancer cells upon re-entry into cell cycle from G1/S or G2/M phase synchronized stages. Its possible cross-talk with cyclin B has also been analyzed at both transcriptional and post transcriptional level. We observed a direct association of cks1 and cdk1 activation and ruled out a cross-talk between cyclin B and cks1. In conclusion, our results indicate that the functional role of cks1 during mitosis may be elicited at the level of cdk1 activation as well as at the level of associated events triggered by active cdk1.

Controlled protein degradation mediated by ubiquitin/proteasome system (UPS) plays a crucial role in modulating a broad range of cellular responses. Dysregulation of the UPS often accompanies tumorigenesis and progression. Ubiquitination of a target protein involves a cascade of enzymes. Importantly, E3 ubiquitin ligases determine the specificity of protein substrates and are themselves the enzymes. They, therefore represent a group of attractive and potentially "drugable" molecular targets for disease intervention in mechanism driven drug discovery. My work is to identify the expression and activation status of Smurf2 (Smad ubiquitin regulatory factor 2), a HECT-type E3-ubiquitin ligase and the signaling pathways in which they are involved in breast cancer and to further investigate whether inhibition of Smurfs by either plant derived or synthetic drugs could be an effective therapeutic regime in breast cancer. We analyzed the expression of Smurf2 in 7 breast cancer cell lines and a high level expression of Smurf2 was detected in MDA-MB-231, NCI-ADR-RES and SKBR3 cell lines.

Endometriosis is a common gynecological disorder that is characterized by the growth of hormone responsive endometrial tissue outside the uterine cavity. This disease owns a unique pathology of a benign proliferative growth process yet having the propensity to invade the normal surrounding tissues. Though several theories have been proposed to explain the etiology of this disease it is still enigmatic. Recent studies have suggested that the endometrial stem/progenitor cells are responsible for establishment of endometriotic implants. The interaction between these progenitor cells and niche cells is crucial for the normal physiology of endometrium and hence a dysregulation in this leads to disease conditions. We aim to study the role of endometrial stem/progenitor cells in the pathogenesis of endometriosis with special emphasis on the notch signaling pathway which is known to be indispensible for stem cells as a communication channel.

Forkhead box (Fox) proteins are family of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. A loss or gain of Fox function can alter cell fate and promote tumorigenesis as well as cancer progression. I work on the functional significance of foxm1 b in eliciting cdk1 expression and in regulating the ubiquitin proteasome pathway. FoxM1 is a proliferation-associated forkhead transcription factor which regulates genes important for G1/S-transition, S-phase progression, G2/M transition and progression through M-phase. Abnormal up regulation of Fox M1 has been reported in majority of solid human cancers including liver, breast, lung, prostate, cervix, colon, pancreas and brain. In this study, we would like to delineate the functionally relevant interaction which might exist between Foxm1 and cdk1 at transcriptrional and translational level. In depth understanding of the functional significance of FoxM1 and its interactome will provide better insights into the regulatory mechanisms involved in cell cycle and ubiquitination pathway. Thereby this study may pave the way for the identification of small molecules in targeted cancer therapy.