About 15-20% of breast cancer patients fall under the basal-like category, which represent a diverse subtype that is characterized by tumors that are more aggressive conferring poor prognosis. Deaths from these carcinomas result from metastatic spread of the disease to distant sites and from therapeutic resistance, which results in the relapse of cancers into more aggressive forms that are difficult to contain. Both these properties are attributed to their cellular heterogeneity that arises through various mechanisms including clonal evolution and the presence of cancer stem cells (CSCs). The epithelial-to-mesenchymal transition (EMT) is one program that we have shown to be responsible for the generation of cells that have CSC-like properties. Our current proposal aims to induce differentiation of these CSCs through the induction of a mesenchymal- to-epithelial transition (MET). To do this, we carried out a screen to identify compounds that are capable of inducing the transcription of E-cadherin, a hallmark of the epithelial/non-CSC state, in cells that are more mesenchymal/CSC-like. Through this screen we identified Forskolin, an activator of cAMP, to be able to induce E-cadherin transcription and a reversion of the mesenchymal/CSCs to a more benign epithelial state. Through this proposal we aim to uncover the mechanism by which cAMP-elevating agents are able to induce an MET by complete characterization of the essential downstream components of signaling, namely Protein Kinase A (PKA) and its downstream substrates. We also aim to uncover specific GPCR- ligand pairs that could modulate cAMP levels thereby serving to maintain the epithelial state. Through extensive in vivo studies, we plan to develop a novel targeting strategy that combines the use of cAMP- elevating agents as adjuvants to chemotherapeutic drugs. This would serve as a means of depleting CSCs through cAMP-mediated differentiation as well as non-CSCs by hemotherapy in basal-like breast cancers.
Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer;with over 230,000 cases of invasive breast cancer reported every year in the United States. Majority of deaths attributed to metastatic spread of the disease to distant sites and their resistance to chemotherapy. Our current study aims to understand the mechanisms by which cancer cells develop chemotherapy resistance and ability to metastasize, in order to develop novel therapies that can effectively be used to render them benign and more sensitive to current treatment regimes.
|Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17|
|McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27|
|Tam, Wai Leong; Lu, Haihui; Buikhuisen, Joyce et al. (2013) Protein kinase C * is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24:347-64|
|Guo, Wenjun; Keckesova, Zuzana; Donaher, Joana Liu et al. (2012) Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148:1015-28|
|Valastyan, Scott; Weinberg, Robert A (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275-92|
|Kojima, Yasushi; Acar, Ahmet; Eaton, Elinor Ng et al. (2010) Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A 107:20009-14|
|Taube, Joseph H; Herschkowitz, Jason I; Komurov, Kakajan et al. (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A 107:15449-54|
|Valastyan, Scott; Chang, Amelia; Benaich, Nathan et al. (2010) Concurrent suppression of integrin alpha5, radixin, and RhoA phenocopies the effects of miR-31 on metastasis. Cancer Res 70:5147-54|
|Valastyan, Scott; Reinhardt, Ferenc; Benaich, Nathan et al. (2009) A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137:1032-46|
|Valastyan, Scott; Benaich, Nathan; Chang, Amelia et al. (2009) Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis. Genes Dev 23:2592-7|
Showing the most recent 10 out of 30 publications