- Breast Cancer
- Signal Transduction
- Epithelial-mesenchymal Transition
- Metastatic Dormancy
The process of mammary tumorigenesis and its assortment of associated genetic and epigenetic events enable newly malignant cells to evade the cytostatic activities of TGFβ, which normally functions as a potent antagonist of mammary tumorigenesis. As breast cancer cells continue down the evolutionary path towards advanced malignancy, they ultimately acquire the ability to transform the cytostatic signals produced by TGFβ into oncogenic activities, including enhanced proliferation, invasion, and metastasis. This peculiar conversion in TGFβ function is known as the "TGFβ Paradox," which underlies the lethality of TGFβ in metastatic breast cancers. Moreover, solving the "TGFβ Paradox" and how it initiates the oncogenic activities of TGFβ remains a fundamental question that directly impacts our ability to pharmacologically target the TGFβ signaling system when treating human malignancies, including those of the breast.
The primary goal of our research is to solve the "TGFβ Paradox" and its relationship to the initiation of epithelial-mesenchymal transition, which couples TGFβ to breast cancer metastasis, and to the selection, expansion, and chemoresistance of breast cancer stem cells. In trying to unravel these mysteries, we combine contemporary techniques in molecular and cellular biology, in biochemistry, and in genomic- and proteomic-based differential gene expression analyses. We also translate our in vitro analyses into animal models capable of interrogating the function of TGFβ in (i) promoting the growth, invasion, and metastasis of mammary tumors produced in mice, and (ii) visualizing the activation of oncogenic TGFβ effectors in developing and progressing mammary tumors in mice. Equally important, we ultimately aim to validate these preclinical findings in analyses involving human-tissue based research, thereby facilitating the initial steps towards translating our basic research findings from the laboratory bench to the patient's bedside.
Major ongoing research efforts are directed at understanding (i) the role of integrins, focal adhesion complexes, and protein tyrosine kinases in regulating the oncogenic activities of TGFβ; (ii) the role of aberrant chromatin dynamics and epigenetic alterations to facilitate the oncogenic and metastatic activities of TGFβ; (iii) the mechanisms whereby c-Abl phenotypically and morphologically normalizes the malignant behaviors of metastatic breast cancer cells; and (iv) the mechanisms whereby altered tumor microenvironments and mechanotransduction impact breast cancer cell response to TGFβ, particularly its regulation of microRNAs. A final focus of the lab seeks to translate and develop these findings into novel cancer chemotherapeutics capable of selectively targeting the oncogenic activities of TGFβ and, consequently, of "normalizing" malignant tissues in such a way that cancer itself can be converted from an acute, symptomatic, and life-threatening disease to one that is chronic, asymptomatic, and manageable through the normal lifespan of affected individuals.
Taylor MT, Davuluri G, Parvani JP, Wendt MK, Plow EF, Schiemann WP* and Sossey-Alaoui K*. Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat. 2013 Nov;142(2):341-53. *Co-corresponding Authors.
Lee, Y-H and Schiemann WP. Chemotherapeutic targeting of the transforming growth factor-β pathway in breast cancers. Breast Cancer Manage. 2: in press, 2014
Wendt MK and Schiemann WP. Longitudinal bioluminescent quantification of three dimensional cell growth. Bio-protocol. In press, 2013.
Parvani, JG and Schiemann WP. Sox4, EMT programs, and the metastatic progression of breast cancers – Mastering the masters of EMT. Breast Cancer Res. 15: R72, 2013. *Highly Accessed.
Parvani JG, Galliher-Beckley, AJ, Schiemann BJ and Schiemann WP. Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β. Mol Biol Cell. 2013 Nov;24(21):3449-59.
Balanis, N, Wendt MK, Schiemann BJ, Wang, Z, Schiemann WP* and Carlin, CR*. Epithelial-to-mesenchymal transition promotes breast cancer progression via a fibronectin-dependent Stat3 signaling pathway. J Biol Chem. 288:17954-17967, 2013. *Co-corresponding Authors. *Featured in "Breaking Advances – Highlights from Recent Cancer Literature" in Cancer Res (2012, vol 73:4172).
Morrison, CD, Parvani, JG and Schiemann WP. The relevance of the TGFβ paradox to EMT-MET programs. Cancer Lett. 327: in press. PMID: 23653350, 2013. *8 consecutive months as a "Top 25" download from the Journal Website.
Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D and Schiemann WP. TGFβ upregulates miR-181a to promote breast cancer metastasis. J Clin Invest. 123:150-163, 2013. *Top Story in "Mammary Cell News" volume 4.50, December 20, 2012. *Featured in MDLinx.com (12/12); EurekAlert (12/12); Cleveland Jewish News (12/12); ScienceDaily (12/12); ScienceNewsline (12/12); News Medical (12/12), Health Canal (12/12); Futurity.org (12/12); The Cleveland Leader (12/12); Biotech Daily (1/13); and NewsRX (1/13). *Featured in "Viewpoint" in Breast Cancer Res (2013) 15:305. *Featured in "News & Views – Research Highlights" in Biomarkers in Medicine (2013) 7:204.
Wendt MK, Schiemann BJ, Lee Y-H, Kang Y and Schiemann WP. TGFβ stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer. Oncogene. 32:2005-2015, 2013. *Top Story in "Mammary Cell News" volume 4.24, June 21, 2012. *Featured in MDLinx.com (6/12).
Wendt MK, Tian M and Schiemann WP. Deconstructing the mechanisms and consequences of TGFβ-induced EMT during cancer progression. Cell Tissue Res. 347:85-101, 2012. *Cover and Featured Article
Taylor MA, Lee, Y-H and Schiemann WP. Role of TGFβ and the tumor microenvironment during mammary tumorigenesis. Gene Expr. 15:117-132, 2011.
Balanis N, Yoshigi M, Wendt MK, Schiemann WP and Carlin CR. β3 integrin-EGF receptor crosstalk activates p190RhoGAP in mouse mammary epithelial cell. Mol Biol Cell. 22:4288-4301, 2011.
Yori JL, Seachrist DD, Johnson E, Lozada KL, Abdul-Karim FW, Chodosh LA., Schiemann WP and Keri RA. Kruppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer. Neoplasia. 13:601-610, 2011.
Raju R, Nanjappa V, Balakrishnan L, Radhakrishnan A, Thomas JK, Sharma J, Tian M, Palapetta SM, Subbannayya T, Sekhar NR, Muthusamy B, Goel R, Subbannayya Y, Telikicherla D, Bhattacharjee M, Pinto S, Syed S, Srikanth MS, Sathe GJ, Ahmad S, Chavan SN, Kumar GSS, Marimuthu A, Prasad TSK, Harsha HC, Rahiman BA, Ohara O, Bader GD, Mohan SS, Schiemann WP and Pandey A. NetSlim: High-confidence curated signaling maps. Database (Oxford). 2011 Sep 29;2011:bar032
Wendt MK, Taylor MA, Schiemann BJ and Schiemann WP. Downregulation of epithelial cadherin is required to initiate the metastatic outgrowth of breast cancer. Mol Biol Cell. 22:2423-2435, 2011. *See Faculty of 1000
Wendt MK, Molter J, Flask, CA and Schiemann WP. In vivo dual substrate bioluminescent imaging. J Vis Exp. 56:e3245, DOI: 10.3791/3245, 2011.
Parvani JG, Taylor MA and Schiemann WP. Noncanonical TGFβ signaling during mammary tumorigenesis. J Mammary Gland Biol Neoplasia. 16:127-146, 2011. *6 consecutive months as a "Top 5" download from the Journal Website
Taylor MA, Amin J, Kirschmann DA and Schiemann WP. Lysyl oxidase contributes to mechanotransduction-mediated regulation of transforming growth factor-β signaling in breast cancer cells. Neoplasia. 13:406-418, 2011. *Cover and Featured Article
Tian M, Neil JR and Schiemann WP. Transforming growth factor-β and the hallmarks of cancer. Cell Signal. 23:951-962, 2011.
Tobi M, Kim M, Zimmer R, Hatfield J, Kam M, Khoury N, Carville A, Lawson MJ, Schiemann WP and Thomas P. Colorectal cancer in the Cotton Top Tamarin (Saguinus Oedipus): How do they evade liver metastasis? Dig Dis Sci. 56:397-405, 2011.
Lee Y-H and Schiemann WP. Fibromodulin suppresses nuclear factor-κB activity by inducing the delayed degradation of IκBα via a JNK-dependent pathway coupled to fibroblast apoptosis. J Biol Chem. 286:6414-6422, 2011.
Allington TM and Schiemann WP. The Cain and Abl of epithelial-mesenchymal transition and transforming growth factor-β in mammary epithelial cells. Cells Tissues Organs. 193:98-113, 2011.