Our lab is currently working on BRCA1 mutated breast tumors in transgenic mouse models.

Mutation in BRCA1 gene leads to the development of mammary tumors. We aim to produce a BRCA1 knock out (KO) mouse model by crossing the two transgenic mouse models – WAP CRE and BRCA1 floxed mice. The crossing of these mice leads to the development of BRCA1 KO progeny by the Cre-loxP recombination system. The breeding of the WAP-CRE and BRCA1 floxed transgenic mice is being done at the Transgenic Knock-out facility, Centre for Cellular and Molecular Biology, Hyderabad, India. Generation of knockouts has been completed by mating of WAP-CRE transgenic mice with BRCA1 floxed transgenic mice to produce BRCA1 knock out mice which develop tumor of the breast at the lactating stage.

Functional characterization of plant derived quinones and their combinations- studying the molecular signature of apoptosis using invivo strategies.

Rakesh S Nair, Priya Srinivas Priya Srinivas
Project in collaboration with Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India
The in vivo model seems to deliver us the efficient tumor markers which could help to design better drug systems. We have to provide substantial ex vivo/in vivo evidence for translating the functional signature of apoptosis attributed by the plant derived lead molecules. We are studying the efficacy of brca1 mutated breast tumors and its dynamics over growth retardation in the presence of standard chemotherapeutic agents and other chemo sensitivity augmenting factors in xenograft models and BRCA1 knocked out transgenic models.

Isolation, Characterization and Therapeutic interventions of Breast cancer Stem Cells from BRCA1 Knockout Mouse Models.

Veena Somasundaram, Priya Srinivas
Project in collaboration with Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India
BRCA1 germ line mutations have been identified in nearly 50% of hereditary breast cancers and approximately 80% of cases with both hereditary breast and ovarian cancers. Decreased BRCA1 expression due to hypermethylation of the BRCA1 promoter or loss of BRCA1 allele has been reported in 30-40% of sporadic breast cancers as well. Therefore, BRCA1 may play a cardinal role in breast cancer development. The role of BRCA1 in human mammary stem cell fate has been examined using both in vitro systems and humanized NOD/SCID mouse model and it has been found that BRCA1 defect increases stem-like behaviour in the normal human mammary cells. Thus, BRCA1 is a regulator of mammary stem cell fate. It has been reported that mouse mammary tumors induced by conditional deletion of BRCA1 respond to therapy with doxorubicin or docetaxel but eventually become resistant to the drug. Thus, there exists a cellular sub-compartment within the tumor which remains resistant to therapy and causes the relapse. This sub set of cells shows “stem-like” behaviour. These cells if isolated and characterized may provide a useful model for drug development for improving the existing treatment regimens

Designing of Metal based anticancer molecules functionally mimicking standard chemotherapeutic agents.

Rakesh S Nair, Priya Srinivas
Project in collaboration with Cochin University of Science and Technology, Cochin, India
To succeed in the therapy, the increased susceptibility of malignant cells to pro-apoptotic action of chemotherapeutic agents exceeding that of normal counterparts would be necessary. However, in tumor cells the apoptotic pathways are frequently misregulated due to inactivation or down-regulation of pro-apoptotic genes, or as a consequence of over expression of anti-apoptotic factors. Therefore, the application of new agents possessing higher selectivity towards malignant cells is necessary. The cancer cells show a primary or acquired resistance to cisplatin. Therefore, extensive effort to develop novel cisplatin analogs with equivalent or greater antitumor activity and a lower toxicity has been made. This made us to develop anticancer molecules which are coordination complexes of transition metal series. Application of combinatorial drug chemistry and cancer biology for screening the lead molecules are used in this study.

Current Research Projects

Sl. No	Title of Project	Funding Agency
1	Mechanisms of anticancer activity of emodin/aloe emodin: effects on cell growth, angiogenesis and metastasis in human colon cancer cells (Co-PI)	DAE, Govt. of India
2	"Studies on matrix metalloproteinsase (MMP) gene transcription by nitric oxide: mechanism of MMP gene induction in human colon cancer cells" (Co-PI)	DBT, Govt. of India

Completed Research Projects

Sl. No	Title of Project	Funding Agency
1	Molecular evidence for potential use of plumbagin in brca1 blocked/ mutated cancers (I)*	DBT Program Support Phase III, Govt. of India
2	Effects of phytoestrogens (emodin & genistein) on BRCA1 blocked ovarian cancer cells (PI)	ICMR, Govt. of India
3	"Potential role of plumbagin as an anticancer agent in brca1 blocked ovarian cancer cells: comparison with standard chemotherapeutic agents" (PI)	DST, Govt. of India
4	"Selective gene expression by plumbagin in BRCA1 blocked ovarian cancer cells: An analysis by subtractive hybridization" (PI)	KSCSTE, Govt. of Kerala