Article Title

Identification of New Therapeutic Drugs for Triple-Negative Breast Cancer

Authors

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Abstract

Background: The development of cancer is a multistep process of sequential genetic alterations in oncogenes and tumor-suppressor genes, making it extremely challenging to find a cure for cancer. In the case of breast cancer, patients diagnosed with triple-negative breast cancer (15%–20%) have the worst survival outcome and no new treatment options. It is characterized by having no or low expression level of three genes, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2), which makes it more difficult to develop therapeutic agents. A new targeting approach is greatly needed to identify novel drug targets for triple-negative breast cancer.

Purpose: We have taken a drug-targeting approach to identify new drug targets for triple-negative breast cancer. We propose to test Food and Drug Administration (FDA)-approved drugs on patient-derived triple-negative breast cancer primary cells generated from patient tissue.

Methods: Residual tissue samples from triple-negative breast cancer surgery were processed and the dissociated cells were grown in a specific tissue-culture medium containing supplements. A triple-negative primary cell line was authenticated by an independent company to demonstrate that it was a true cell line (DNA fingerprinting). A panel of FDA-approved drugs was tested on the primary cell line to identify new therapeutic drugs. Molecular and cellular assays, including cell proliferation and cytotoxicity, were used to determine the effect of the drugs on the cells. Specific cell signaling pathways were investigated to discover the mechanism of action.

Results: We have successfully established a triple-negative breast cancer patient-derived primary cell line, the first at Aurora Health Care. The triple-negative cells are negative for the three known receptors (ER, PR, HER2) but positive for cytokeratin 5 and 8/18 by immunocytochemical staining. We have identified several potential FDA-approved drugs that inhibit triple-negative cells from growing. Selected drugs are being further investigated for their mechanism of action.

Conclusion: To address the limited treatment options for patients diagnosed with triple-negative breast cancer, we have taken a drug-targeting strategy. Repurposing FDA-approved drugs for triple-negative breast cancer could be a powerful approach to discovering new therapeutics to improve patient care.