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Lalage M. Wakefield, D.Phil.
Tumor Suppressor and Pro-oncogenic Activities of Transforming Growth Factor-betas in Breast Cancer.
Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that play complex roles in the development of many different tumor types. The prevailing hypothesis is that TGF-betas have tumor suppressor activity early in the carcinogenic process, but that in the later stages, tumor suppressor activity is lost and pro-oncogenic activities come to dominate. Both facets of TGF-beta biology involve the tumor stroma as well as the tumor parenchyma, and affect multiple biological processes. TGF-beta pathway antagonists are now in early phase clinical trials with the goal of blocking the pro-oncogenic effects of TGF-beta, so understanding the dual role of TGF-beta will be critical to the safe and effective development of these agents. Our research program uses a variety of approaches in preclinical mouse model systems to address the role of TGF-betas in breast cancer, and to elucidate underlying mechanisms. Where possible, we apply this knowledge to further the development of therapeutic strategies that target the TGF-beta pathway.
Probing the dual role of TGF-beta in breast cancer. Our major goal in this part of the program is to elucidate biological and molecular mechanisms underlying the dual role of TGF-beta. Here we are specifically focused on the effects of TGF-beta on the tumor parenchyma, and much of our current work uses a powerful xenograft model system of breast cancer progression, based on the MCF10A human breast epithelial line and its transformed derivatives. This model exemplifies the dual role of TGF-beta in that the premalignant and early malignant lines show tumor suppressor responses to TGF-beta while the most aggressively malignant line responds to TGF-beta with enhanced metastasis. We are applying integrated genomic approaches to this model to identify major changes in molecular context that influence the output of the TGF-beta signal. Key findings are then replicated in primary human breast cancer cell cultures. One goal is to develop TGF-beta-related gene signatures that can identify which aspect of TGF-beta dominates in a given tumor. Importantly, we have identified a role for TGF-beta in regulating the cancer stem cell population, and we have developed a novel fluorescent stem cell reporter which allows us to visualize the cancer stem cell in its native habitat with contextual cues intact. Understanding how TGF-beta modulates cancer stem cell dynamics should give new insights into how to target this therapy-resistant tumor cell subpopulation.
TGF-beta antagonists for the suppression of metastasis. Advanced human tumors characteristically show elevated TGF-beta expression, which correlates with poor prognosis. We and others have previously shown that antagonizing TGF-beta therapeutically can suppress tumor metastasis without the expected deleterious effects on normal homeostasis and early tumorigenesis. As a result, anti-TGF-beta therapeutics are now in Phase I or II clinical oncology trials. Our goal in this part of the program is to use preclinical models to elucidate underlying mechanisms and support the clinical development of these agents. Mechanistically we have shown that the therapeutic efficacy of anti-TGF-beta antibodies involves multiple small effects on many different cellular compartments (the Death by a Thousand Cuts model) that aggregately result in the generation of a more hostile tumor microenvironment. We have assembled a large panel of transplantable mouse models of metastatic breast cancer and demonstrated heterogeneous responses to TGF-beta antagonism across the panel. Future directions with this project include (i) mechanisms underlying adverse responses to TGF-beta antagonism, (ii) development of predictive biomarkers for patient selection, and (iii) improving therapeutic efficacy through rational combinations with other therapeutics.
Our collaborators include Dominic Esposito, ATP, FNLCR; Miriam Anver, SAIC-Frederick; Stephen Hewitt, NCI-ATC; Jay Berzofsky, Kent Hunter, Maxwell Lee and Howard Yang, NCI; Rea Ravin, NICHD; William Smith, Suburban Hospital.
This page was last updated on 11/26/2013.