APPLICATIONS OF TECHNOLOGY:

• Creating therapies by targeting SATB1 promoters
• Developing methods to reverse drug resistance of aggressive breast cancer
• Using SATB1-specific inhibitors to treat breast cancer
• Screening for metastatic-prone breast cancers
• Designing assays to detect SATB1 expression in aggressive breast cancer cells

ADVANTAGES:

• A fundamental and powerful target for new diagnosis, prognosis, and treatment methods in invasive breast cancers
• May be expressed in other aggressive forms of cancer
• Allows early detection of cells prone to metastasis
• Potential to target drug resistant aggressive breast cancer
• Offers a new assay to detect SATB1 protein and transcription levels in the prediction or marking of aggressive breast cancers

ABSTRACT:

Researchers from Berkeley Lab are the first to discover that the SATB1 protein is a key determinant in the acquisition and maintenance of the metastatic phenotype of breast cancer, and that SATB1 may be used as a new diagnostic and prognostic marker, and therapeutic target, for aggressive breast cancers.

In addition to discovering that the expression of SATB1 is an excellent indicator of aggressive breast cancer cells, the Berkeley Lab research team also learned that SATB1 protein expression in aggressive breast cancer can be down-regulated, thus preventing a cell from becoming metastatic.

SATB1 is an especially powerful target for breast cancer because the protein is a genome organizer that orchestrates the expression of hundreds of genes by regulating higher-order chromatin structure and epigenetic status of target gene loci. SATB1 has a potential to promote chromosomal instability.

The Berkeley Lab research team examined the SATB1 protein expression levels in various breast cancer cell lines, and human breast cancer tissue specimens from approximately 1,000 patients, and found that SATB1 expressions are detected mainly in highly aggressive late-stage breast cancers, but not in normal breast tissue cells or nonaggressive breast cancers. The Berkeley Lab researchers successfully linked SATB1 expression levels to a breast cancer cell’s progression from a normal to invasive phenotype. Since SATB1 appears strongly connected to aggressive breast cancers, it promises to be an effective prognostic and diagnostic marker for detecting aggressive cancer cells.

The researchers studied over 1,000 breast cancer specimens with known follow-up records. Among these specimens, Kaplan-Meier survival analysis of 985 ductal carcinoma specimens revealed a correlation between higher SATB1 expression levels and shorter overall survival times (P<0.0001). This was also true for all breast cancer types (1,318 specimens) except medullary cancer. Multivariate analysis confirmed that SATB1 is an independent prognostic marker for breast cancer (P<0.0001). This means that expression of SATB1 in a subset of primary breast tumors at early clinical stages prior to lymph node metastasis has high prognostic significance, independent of the lymph node status (P<0.0001), and may be useful in predicting the likelihood of disease progression in patients with early-stage breast cancer.

Research indicates that SATB1 is a key determinant for the acquisition and maintenance of the metastatic phenotype of breast cancer. When the Berkeley Lab researchers treated late-stage aggressive cancer cells (MDA-MB-231 and BT549) with designed target sequences for SATB1-shRNA to reduce SATB1 expression, the cells’ phenotypes reverted from invasive to noninvasive, and their tumor growth was abrogated in vivo. Conversely, ectopic SATB1 expression in nonaggressive (SKBR3) cells made these cells acquire metastatic activity in vivo.

Drug resistant aggressive breast cancer cells can restore their sensitivity to drugs by reducing SATB1 expression. Therefore, targeting SATB1 expression is potentially useful in treating drug resistant cancer cells.

Before the Berkeley Lab research team’s discoveries of the diagnostic, prognostic, and therapeutic benefits of controlling SATB1 expression in treating aggressive breast cancers, it was unknown whether a breast cancer cell’s metastatic phenotype in vivo could be reversed to a non-tumorigenetic state. The Berkeley Lab SATB1 marker and target has the potential to be one of the most definitive breast cancer therapeutic targets to date. Therapeutics targeted against SATB1 might include siRNA oligonucleotides, antisense oligonucleotides, peptides, aptamers, and small molecules.

DEVELOPMENT STAGE:  UPDATED for 2010

Berkeley Lab researchers are continuing their work to identify the expression of SATB1 in the bloodstream.

They are also evaluating the following:

• specific promoter usage for SATB1 transcription in breast cancer and leukemia,
• specific post-translational sites to regulate SATB1 activity in promoting metastasis, yielding a therapeutic application,
• the relationship between SATB1 and cancer drug resistance, and
• SATB1 as a marker for other tumors/cancers.

SATB1 determines the gene expression profile to promote breast cancer metastasis.  A) A scheme representing cell morphological changes associated with breast cancer progression starting with a polarized structure, acinus, formed by normal breast epithelial cells to a nonpolar disorganized structure formed by malignant cells.  B) Reversion of cell morphology and restoration of polarity upon SATB depletion from human aggressive MDA-MB-231 cells by RNAi methods.  SATB1 depleted MDA-MB-23 cells (SATB1 siRNA) and host MDA-MB-231 cells were cultured on plastic dish (two dimensional culture, 2D) and on the extracellular matrix (ECM) (three dimensiosnal culture, 3D).  Top panels:  DNA stained by DAPI:blue, Beta-catenin; green, Bottom panels, DNA; blue, integrin alpha6, green.  C) A scheme illustrating genome re-organization by SATB1 once it is expressed in breast cancer cells.  Representative genes (shown by black arrows) known to be highly relevant to breast cancer metastasis are enhanced or induced depending on sATB1 expression.  Tumor suppressor genes are repressed by SATB1. Expression of approximately 1200 genes are altered depending on SATB1 by anchoring gene loci onto the SATB1 nuclear architecture (red oval).

NATURE PUBLICATION : Han, H.-J. , Russo, J. , Kohwi, Y. & Kohwi-Shigematsu, T. Nature 452, 187–193 (2008).

STATUS:

• Published Patent Application. Available for licensing or collaborative research.

REFERENCE NUMBER: IB-2186

SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:

• High Selectivity Peptides for Cancer Therapy, Screening for Cancer Therapies, and Therapy Sensitization, IB-2489

• Comprehensive Prognostic Markers and Therapeutic Targets for Drug-Resistant Breast Cancers IB-2281

• Rac1b: A Highly Selective Marker and Target for Cancer, IB-2167

• Identifying Biomarkers of Physiological Responses to Cancer Cells, IB-2546