Our primary research interest is to elucidate the molecular mechanisms of erbB receptor tyrosine kinase (RTK) family members-mediated signal transduction in breast cancer formation and progression. By understanding the cancer biology of erbB2/erbB3 receptors and the protein-protein interactions among RTKs, we hope to identify novel molecular targets and develop small molecules with therapeutic potential for cancer patients.
While numerous studies demonstrate that erbB2 is one of the most well characterized oncogenes involved in breast carcinogenesis and more recently used as a therapeutic target, there is relatively little study on erbB3 as a molecular target for cancer treatment.In the last 2-3 years, our laboratory has focused on studying the unique biologic features of erbB3 receptor, and published a series of articles indicating that erbB3 may be an important molecular target and novel therapeutics targeting erbB3 may enhance the efficacy of erbB2-targeted therapies.
There are currently three areas of investigation in my laboratory:
The role of erbB3 receptor in erbB2-mediated therapeutic resistance.We have reported that specific knockdownof erbB3 expression abrogates erbB2-mediated tamoxifen resistance (Int J Cancer, 120: 1874-1882, 2007). Our recent studies reveal that elevated expression of erbB3 upregulates Survivin to confer paclitaxel resistance in erbB2-overexpressing breast cancer cells, and erbB3 receptor interacts with both erbB2 and insulin-like growth factor-1 receptor (IGF-1R) to form a heterotrimeric complex in Herceptin-resistant breast cancer cells (Cancer Res,in press, 2009). Modern molecular and cellular biological techniques are applied to determine the mechanisms by which erbB3 contributes to erbB2-mediated therapeutic resistance.
Identification of novel erbB3-targeted therapeutics. We have considered the unique biologic features of erbB3 receptors and successfully discovered that the selective class I HDACi SNDX-275 (Syndax Pharmaceuticals, Inc., San Diego, CA) modulates expression of erbB3-targeting miRNAs, and induces apoptosis in erbB2-overexpressing breast cancer cells via downregulation of erbB3 (Cancer Res, 69: 8403-8411, 2009). The ongoing experiments aim to determine whether the potential therapeutics targeting erbB3 (blocking antibodies and SNDX-275) may abrogate or attenuate erbB2-mediated resistances to tamoxifen, paclitaxel, and enhance erbB2-targeted therapies, such as Herceptin and lapatinib.
Epigenetic regulation of Multiple Myeloma (MM). In collaboration with Dr. Choon-Kee Lee (Division of Medical Oncology, Department of Medicine), we are exploring the combinational effects of Bendamustine and SNDX-275 on MM. Bendamustine, a hybrid molecule of purine analog and alkylator, is known to induce cell death by activation of DNA-damage stress response, and induction of mitotic catastrophe and apoptosis. The study proposes combination of bendamustine with SNDX-275 to enhance cell death of MM cells, in particular of the resistant ones to conventional chemotherapeutic agents and to bortezomib.
1. Huang, X.P., Gao, L., Wang, S., McManaman, J.L., Thor, A.D., Yang, X., Esteva, F.J., and Liu, B. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor in breast cancer cells resistant to Herceptin. Cancer Research 70(3):1204-1214, 2010
2. Lee, C-K., Wang, S., Huang, X., Ryder, J., and Liu, B. HDAC Inhibition Synergistically Enhances Alkylator-induced DNA Damage Responses and Apoptosis in Multiple Myeloma Cells. Cancer Letters 296: 233-240, 2010
3. Wang, S., Huang, X., Lee, C-K., and Liu, B. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 29: 4225–4236, 2010
4. Huang, X., Wang, S., Lee, C-K., Yang, X., and Liu, B. HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Letters 2011 Aug 1;307(1):72-9.
5. Ma J, Wang S, Zhao M, Deng XS, Lee CK, Yu XD, Liu B. Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma. BMC Cancer 2011 Jun 16;11(1):255.
6. Liu, B.*, Fan, Z., Edgerton, S.M., Yang, X., Lind, S.E., and Thor, A.D.* Potent Anti-proliferative Effects of Metformin on Trastuzumab-resistant Breast Cancer Cells via Inhibition of ErbB2/IGF-1 Receptor Interactions. Cell Cycle Sep 1, 10 (17): 2959-2966, 2011 *Corresponding authors
7. Cai, B., Wang, S., Huang, J., Lee, C-K., Gao, C., and Liu, B. Cladribine and bendamustine exhibit inhibitory activity in dexamethasone-sensitive and -resistant multiple myeloma cells. American Journal of Translational Research 2013; 5(1):36-46.
8. Wang, L., Huang, Z., Lin H., Li, Z., Hetzel, F.W., and Liu, B. Effects of photofrin-mediated photocytotoxicity on a panel of human pancreatic cancer cells. Photodiagnosis and Photodynamic Therapy, 2013 http://dx.doi.org/10.1016/j.pdpdt.2012.11.001.
9. Wang, S., Huang, J., Lyu, H., Lee, C-K., Tan, J., Wang, J., and Liu, B. Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death & Disease (2013) 4, e556; doi:10.1038/cddis.2013.79