Tumor Suppressor 14-3-3sigma in Breast Cancer Progression

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Aaron Boudreau, B.Sc. -
Award Cycle: 2008 (Cycle 14) Grant #: 14GB-0007 Award: $62,434
Award Type: Dissertation Award
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2008)

The dynamic interplay amongst cells comprising the mammary gland presents a challenge in understanding normal breast biology and how this fine balance is altered in the case of malignancy. Remodeling of the microenvironment by tumorigenic cells is a critical step in cancer progression, with extracellular matrix (ECM) degradation being necessary for invasion into adjacent tissues. The complexity of the breast is reflected in the multiple subtypes of breast cancer that arise within patients. In a cell culture model which recapitulates many features of breast cancer progression(HMT-3522 S1 and T4-2), we recently identified a protein called 14-3-3sigma that becomes highly expressed in malignant T4-2 cells in comparison to their nonmalignant counterpart S1 cells. 14-3-3sigma is a direct transcriptional (gene regulatory) target of the p53 tumor suppressor and is increased in response to chemical or irradiation-induced DNA damage, causing cell cycle arrest at the G2/M checkpoint. As 14-3-3sigma is dogmatically described as a tumor suppressor, the increased expression of 14-3-3sigma in T4-2 cells is compelling and worth investigation as to its potential role in cancer progression.

To address whether 14-3-3sigma is in fact a tumor suppressor or an oncogene in breast cancer, we will measure expression of 14-3-3sigma in tissues obtained from a large group of patients which has been extensively evaluated with histological markers. To try to understand the role of 14-3-3sigma in the HMT-3522 model of breast cancer progression, we will perform a sophisticated screen (affinity capture proteomics) to identify other proteins that bind to 14-3-3sigma in the cell lines. The interacting proteins will hopefully provide clues as to how 14-3-3sigma regulates tumor progression in this model, and we will validate this data in other cell culture models and in data obtained from patients to identify novel functions of 14-3-3sigma in cancer progression.

The overall goal of current breast cancer research is the development of selective, specific, and patient-tailored drugs to minimize unnecessary side effects and risks to patients. In order to achieve this, understanding the biology of the different classes of breast cancer is necessary, and will lead to the identification of potential drug targets (such as 14-3-3sigma) for future research. The proposed experiments aim to fundamentally understand the biology of breast cancer progression, and to validate 14-3-3sigma as a potential “druggable” target to stop cancer progression.

Final Report (2010)

The term “breast cancer” cannot be used to describe a single disease, and rather, describes a collective of at least five disease subtypes each having distinct genetics, response to chemotherapy, clinical outcome, and biology. Understanding the molecular basis of tumor progression among the individual subtypes of breast cancer will allow the eventual development of patient-tailored therapeutics with higher specificity towards individuals.

We previously identified a protein called 14-3-3sigma which becomes highly expressed during malignancy in a culture model of breast cancer progression, and when tumor cell lines were engineered to have reduced expression of 14-3-3sigma, their motility and invasive characteristics were compromised. The goals of the research project were two-fold: to characterize the mechanism by which 14-3-3sigma regulates tumor cell migration and invasion (important prerequisites to metastasis in patients), and to address whether 14-3-3sigma expression is a property of a specific subtype(s) of breast cancer.

During the research, I characterized a novel mechanism by which 14-3-3sigma regulates cell migration and invasion by regulating the homeostasis of the cytoskeleton - the “bones” of a cell which determines cell shape and size, and which is remodeled extensively during migration. Furthermore, I found that while 14-3-3sigma is lost in many breast tumors, it remains highly expressed in a specific subset of carcinomas associated with poor clinical outcome. The discoveries resulting from my research suggest that targeting 14-3-3sigma may be an effective therapeutic strategy in a subset of breast tumors.

Future work will aim to characterize how 14-3-3sigma is regulated, and additionally, to better characterize what role this protein plays during normal mammary gland development and function.

Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices.
Periodical:Cancer Metastasis Reviews
Index Medicus: Cancer Metastasis Rev
Authors: Xu R, Boudreau A, Bissell MJ
Yr: 2009 Vol: 28 Nbr: 1-2 Abs: Pg:167-76

Dissecting regional variations in stress fiber mechanics in living cells with laser nanosurgery.
Periodical:Biophysical Journal
Index Medicus: Biophys J
Authors: Tanner K, Boudreau A, Bissell MJ, Kumar S.
Yr: 2010 Vol: 99 Nbr: 9 Abs: Pg:2775-83