ALK and TGF-Beta Resistance in Breast Cancer
Abstract
Our proposed research aims to address the following Breast Cancer Research Program overarching challenges: (1) Identify what drives breast cancer growth and metastasis; identify why some breast cancers become life threatening metastases; and (2) identify what makes the breast susceptible to cancer development. Our research will help triple-negative breast cancer patients and particularly the relatively rare but the most lethal subtype of breast cancer, called inflammatory breast cancer (IBC), through development of a biomarker for IBC and guidance of IBC treatment. Abnormal or uncontrolled growth of cells leads to cancer formation. Among many factors that control cell growth and death, the transforming growth factor-beta (TGF-beta) is one of the most important tumor-suppressing masters shown to control cell growth and death. Escape from this control is one major reason why human cancers develop. TGF-beta passes its growth-inhibitory information onto proteins called Smads, which are known to suppress tumor growth. The critical roles of Smad4 in tumor suppression have best been demonstrated from the observations that genetic changes in the Smad4 gene have been frequently found in gastrointestinal and pancreatic cancers. However, similar mutations are rare in breast cancer. Thus, the precise regulation of Smad molecules is crucial for breast cell response to TGF-beta signals. Breast cancers, like many other cancers, are resistant to TGF-beta s tumor-suppressing actions. The question is, What is responsible for TGF-beta resistance in breast cancer? We have for the first time discovered that Smad4 can be destroyed by cancer-causing protein ALK. ALK belongs to a family of enzymes that add a phosphate group to proteins (termed phosphorylation). ALK does this on Smad4 and inactivates Smad4 as a tumor suppressor. Importantly, gene amplification and other genetic changes to activate ALK occur in a significant percentage of breast cancer cases (>5%), and especially in IBC and triple-negative breast cancer. IBC differs substantially from non-IBC and usually responds poorly to therapies used in the usual form of breast cancer. Thus, it is important to identify biomarkers and to find potential therapies for IBC. In our proposed studies, we will test our hypothesis that ALK promotes the development of breast cancer and especially IBC partly through blocking Smad4 tumor suppressive actions. We will find out if ALK can truly destroy Smad4 functions in mouse tumor models and human patient xenografts and if ALK is highly correlated with Smad4 phosphorylation in breast cancer. We will carry out studies to dig deeper into the mechanisms and functions of ALK-mediated Smad4 phosphorylation, and we hope to understand better whether removal of ALK activity (either genetically or chemically) can restore the tumor suppressor functions of Smad4. The proposed studies will not only connect the oncogenic function of ALK to the abrogation of Smad4 tumor suppressive pathway in IBC for a better understanding of this deadly disease, but also have the potential to identify Smad4 tyrosine phosphorylation by ALK as a new therapeutic biomarker or target for cancer prevention and treatment. Equally important, our studies will help better understand new and/or side effects of ALK inhibitors such as Food and Drug Administration-approved crizotinib (sold as Xalkori by Pfizer) in clinically treating malignancies caused by aberrant ALK activation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510650
Entities
People
- Xin-Hua Feng
Organizations
- Baylor College of Medicine
- United States Army