Abstract
We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.
Highlights
Triple-negative breast cancer (TNBC), up to 15% of breast cancer, is defined as absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression
We demonstrated that pharmacological decrease of Cancerous inhibitor of protein phosphatase 2A (CIP2A), thereby increased phosphatase 2A (PP2A) activity and subsequent inactivation of the p-Akt signaling, inhibited proliferation and induced apoptosis in breast cancer cells [13, 14]
Only lapatinib demonstrated CIP2A inhibition, and both anti-epidermal growth factor receptor (EGFR) or anti-HER2 monoclonal antibodies had no effects on CIP2A (Figure 1B, right)
Summary
Triple-negative breast cancer (TNBC), up to 15% of breast cancer, is defined as absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression. The comprehensive review by Khanna et al [15] summarized that CIP2A overexpression is found in almost all solid cancers and in some hematological malignancies such as acute and chronic myeloid leukemia, and that high expression of CIP2A has been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as doxorubicin, cisplatin, bortezomib, erlotinib, Checkpoint Kinase 1 inhibitors and pro-senescence based therapies such as vinka alkaloids chemotherapy and several in development small molecules [15, 17, 18] Together, these data suggest that CIP2A plays an important role in breast cancer cells and that targeting CIP2A could be a new therapeutic option
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