Fundamental research on the development of treatment for triple negative breast cancer

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Expression levels of estrogen receptor, progesterone receptor and HER2 in breast cancer tissues have been routinely measured in clinics to predict responses to endocrine therapy and anti-HER2 therapy. Breast tumors expressing none of these three receptors are named as triple negative breast cancer (TNBC). TNBC responds to neither endocrine therapy nor anti-HER2 therapy, is biologically aggressive, tends to recur earlier, and renders a poor prognosis. These findings prompt us to develop new treatment strategies against TNBC. First, we investigated a protein expression profile of various genes related to TNBC characteristics in a panel of human breast cancer cell lines. Next, we studied antitumor activity, effects on cell cycle progression, apoptosis and cancer stem cell population induced by DNA-damaging cytotoxic agents and molecular targeting agents in the panel of breast cancer cell lines. These experimental results have revealed that a Src signal inhibitor, dasatinib and a DNA-damaging agent, etoposide show potent antitumor effect on breast cancer cells of basal B subtype associated with G1-S blockade and induction of apoptosis for dasatinib or G2/M retardation and induction of apoptosis for etoposide, respectively. It is indicated for the first time that dasatinib reduces a proportion of putative cancer stem cells. We also investigated clinical significance of activation of Src signaling using immunohistochemistry in patients with breast cancer. The results of this study have indicated that activation of Src signaling may increase metastatic potential of breast cancer cells.