Editors' ChoiceBreast Cancer

Strike Three: Positive Progress on the Triple Negative

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Science Translational Medicine  23 Mar 2011:
Vol. 3, Issue 75, pp. 75ec39
DOI: 10.1126/scitranslmed.3002405

Baseball fans know that a row of dangling Ks—indicating strike-outs—means a good night for the pitcher. Researchers have pitched strikes at two of three kinds of breast cancers by identifying disease-driver mutations that can be targeted by currently available therapies. These mutations manifest as the overproduction of steroid hormone receptors for estrogen and progesterone or of the receptor tyrosine kinase HER2 (human epidermal growth factor receptor 2). However, ~20% of breast cancer diagnoses are termed triple-negative—an aggressive heterogeneous group of cancers that carry the poorest prognosis and lack the hallmark characteristics of the other two classes of mammary tumors. Now, researchers may have pitched the third strike. With an unbiased functional screen, Sun et al. identified mutated versions of a tumor suppressor, the protein tyrosine phosphatase PTPN12, in triple-negative breast cancers (TNBCs).

Using a genetic screen for suppressors of cellular transformation, the researchers found that the PTPN12 gene is frequently deleted, mutated, or silent in TNBCs. Histological staining of a cohort of 185 human primary breast cancers revealed that the PTPN12 protein was absent from 60% of TNBCs as compared with 9% of cancers that overexpressed HER2. PTPN12 is involved in the regulation of an old rival in the breast cancer field—the HER2/EGFR (epidermal growth factor receptor) pathway. Loss of PTPN12 enabled human breast epithelial cells to proliferate and transform into malignant cells; this conversion was in part dependent on HER2 and EGFR. Lastly, restoring functional PTPN12 in TNBC cells resulted in a substantial reduction in the tumorigenic and metastatic potential of these cells. Thus, PTPN12 appears to suppress the transformation, tumorigenesis, and metastasis of TNBCs by inhibiting multiple oncogenic tyrosine kinases.

Although PTPN12 appears to regulate the EGFR/HER2 pathway, pharmacological inhibitors of these receptors have failed to show clinical efficacy for TNBCs. In an attempt to uncover additional proteins that are regulated by PTPN12, the research group identified platelet-derived growth factor receptor β (PDGFR-β), another receptor tyrosine kinase that modulates cell growth and division. The authors then used a combination therapy approach by treating TNBC cells with lapatimib (which inhibits HER2 and EGFR) and sunitimib (a more broadly acting tyrosine kinase inhibitor that blocks PDGFR-β function) and demonstrated that the tumorigenic and metastatic potentials of PTPN12-deficient TNBC were severely impaired.

Taken together, the findings of Sun and colleagues suggest that PTPN12 exerts its tumor suppression effect by regulating a network of downstream protein tyrosine kinase receptors. Thus, the treatment of tough TNBCs may require a unique combination of tyrosine kinase inhibitors. More exciting than a home run, researchers can now test whether kinase inhibitors that are currently used in the treatment of other cancers are efficacious in the context of this poorly understood and aggressive form of breast cancer.

T. Sun et al., Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. Cell 144, 703–718 (2011). [Abstract]

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