SATB1: a Fundamental Prognostic Marker and Therpeutic Target for Metastatic Breast Cancer


Published in Nature, March 2008. See link below.
Screening for metastatic-prone breast cancers

Using SATB1-specific inhibitors to treat breast cancer

Designing assays to detect SATB1 expression in aggressive breast cancer cells

Creating therapies for genes that express SATB1

Provides a fundamental and powerful target for breast cancer therapy, since SATB1, once it is expressed in breast cancer, reprograms and orchestrates the expression a large number of genes that promote tumor growth and metastasis.

Promises new diagnosis, prognosis, and treatment methods through the detection of a single protein in invasive breast cancers, and possibly other aggressive forms of cancer

Allows early detection of cells prone to metastasis

Provides more accurate identification of patients who would benefit from aggressive treatments, regardless of lymph node status

Offers a new assay to detect SATB1 protein and transcription levels in the prediction or marking of aggressive breast cancers

Researchers from Berkeley Lab and Fox Chase Cancer Center 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. SATB1 is an especially powerful target for breast cancer because the protein is a genome organizer which orchestrates the expression of hundreds of genes by regulating higher-order chromatin structure and epigenetic status of target gene loci.

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 Berkeley Lab research team studied >1000 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 (1318 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.

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 can be down-regulated, thus preventing a cell from becoming malignant. When the Berkeley Lab researchers treated late-stage aggressive cancer cells (i.e., MDA-MB-231 and BT549) with designed target sequences for SATB1-shRNA, 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. These results indicate that SATB1 is a key determinant for the acquisition and maintenance of the metastatic phenotype of breast cancer.

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.

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).

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