Research

1. Elucidate critical mechanism by which the tumor microenvironment controls breast cancer stem cell (CSC) to promote tumor progression: Epigenetic control plays a key role in regulation of tumorigenesis in response to microenvironmental stimuli; however, the regulatory mechanism involved in the process is largely unclear. Our previous work revealed that the expression of a critical epigenetic regulator EZH2 was transcriptionally upregulated by the hypoxic microenviroment (Cancer Cell, 2011). Another two of our studies also showed that microRNA-205 (miR-205) was repressed by Jagged1, a ligand shown to be secreted from the breast tumor stroma (Journal of Clinical Investigation, 2014), while microRNA-200c (miR-200c) was down-regulated by leptin, secreted by adipocytes, the most abundant cell type surrounding breast epithelia (Cancer Research, 2015). Overexpression of EZH2 or suppression of miR-200c/miR-205 led to an expansion of the CSC population and breast tumor progression. Together, these findings elucidate intricate regulation of CSCs in response to different microenviromental stimuli, providing promising therapeutic targets for eradicating breast cancer.

A proposed model illustrating the leptin–STAT3–G9a–miR-200c regulatory axis plays a critical role in governing the CSC traits in response to microenvironmental adiposity, contributing to breast tumor progression.

2. Reveal key intrinsic component and mechanism governing the plasticity of epithelial-mesenchymal phenotype and the stem cell fate determination: Epithelial mechenchymal transition (EMT) has recently been linked to stem cell phenotype. However, the molecular mechanism involving regulation of the plasticity of EMT-MET and stemness-differentiation (cell fate) remains elusive. We discovered that tumor suppressor p53 plays a role in regulating both EMT and EMT-associated stem cell properties through transcriptional activation of microRNAs involved in regulation of stemness (miR-200c, miR-183 and miR-205). Loss/mutation of p53 in mammary epithelial cells leads to decreased expression of these microRNAs and activates EMT program, accompanied by the generation/expansion of the stem cell-like population (Nature Cell Biology, 2011). Our other study further revealed that loss of miR-205 led to EMT in mammary epithelial cells with disrupted epithelial cell polarity, and also enhanced symmetric division of mammary CSCs to expand the CSC pool (Journal of Clinical Investigation, 2014). As a result, these findings provide important therapeutic implications to eradicate CSCs through activation of p53 or miR-205 pathway. 

A proposed model illustrating that jagged1-NOTCH signaling downregulates miR-205 and loss of miR-205 promotes self renewal and SD through constitutive activation of NOTCH2 and ZEB1, leading to expansion of stem cell and tumor stem cell populations.

3. Uncover how advantageous genomic aberrations are acquired for generation or expansion the CSC pool: It has been proposed that an aggressive secondary CSC population arises from a primary CSC/stem cell population through acquisition of genomic mutations and drives cancer progression. However, critical mechanism involved in the regulation of the generation or expansion of CSCs remains unclear. Our previous study identified a mechanism by which overexpression of the Polycomb protein EZH2 silenced the DNA damage repair protein RAD51, leading to accumulation of recurrent RAF1 gene amplification in breast CSCs to promote CSC expansion (Cancer Cell, 2011). Another previous work also showed that PTEN deletion in hematopoietic stem cells led to a recurring chromosomal translocation that resulted in aberrant overexpression of the c-myc oncogene to promote the formation and expansion of leukemic stem cells (Nature, 2008). As a result, these studies provide new therapeutic strategies for elimination of CSCs (e.g. RAF1 inhibitor).

4. Discovery of CSC fate manipulating compounds as new anti-cancer drugs: We are employing an innovative phenotypic robotic high throughput screening platform for discovery of new anti-cancer drugs that can alter the CSC fate (from self-renewal to lineage commitment) to deplete the CSC pool so as to eradicate breast cancer.

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