Research On Anti-breast Tumor Activity Of Two Small Compounds

Breast cancer is among the most frequent type of cancer in women. The2013U.S. statistics shows that breast cancer bears the highest incidence rate and ranks as the second cause of death from cancer overall, only after lung cancer. With the improvement of medical diagnosis and therapeutic strategies, breast cancer incidence and mortality rate have fallen to a decline. However, there are hundreds of thousands of women who die from breast cancer each year. It is the metastasis instead of primary site of breast cancer that causes the patient deaths. Moreover, studies also indicate that metastasis is responsible for90%of cancer mortality. Although a few therapeutic agents have been in clinic, novel medications, especially those targeting breast cancer metastasis, is in urgent need.This thesis involves the preclinical research of two small molecule compounds on breast cancer.Part one demonstrates that cucurbitacin E (CuE), a Chinese herbal monomer, impairs breast cancer metastasis through targeting breast cancer cell migration and invasion. Cucurbitacin E (CuE) is a tetracyclic triterpenes natural product originally isolated from Cucurbitaceae. It has been showed that CuE possesses anti-inflammatory, anti-virus, anticancer and anti-angiogenesis effects. However, the function of CuE on tumor metastasis and its related molecular mechanism have not yet been investigated. We found that CuE significantly inhibits breast tumor spontaneous and experimental metastasis to the lung without affecting apoptosis or proliferation of inoculated breast cancer cells, suggesting CuE blocks breast cancer metastasis by targeting tumor cell migration and invasion. Our mechanistic study indicated CuE markedly blocks tumor cell actin polymerization and decreases Arp3expression. In addition, overexpression of Arp3could partially rescue the actin depolymerization caused by CuE. MMPs are essential regulators in tumor invasion and metastasis. Our data revealed CuE blocks Src/FAK/Racl/MMPs signaling pathway. These results provided first evidence of a novel role for CuE as a potential candidate for treating breast cancer metastasis.Part two focuses on a novel histone deactylase inhibitor, YF479. We find YF479could inhibit breast cancer growth, metastasis and recurrence. Cancer has conventionally been considered as a disease involving genetic defects. However, epigenetic changes, such as DNA methylation and histone acetylation, ubiquitination and glycosylation also contribute to tumor development. The reversible change of epigenetics makes it possible for cancer therapy. In normal cells, histone acetylation (regulated by histone acetytransferase,HAT)and deacetylation(regulated by histone deactylase, HDAC) are in dynamic balance. Abnormal activation of HDAC is closely related to breast cancer and HDAC is now considered as a promising target of breast cancer. We screen our compound library to identify a novel HDAC inhibitor, YF479. The acetylation of H3, H4is increased after treatment with YF479. YF479could also induce breast cancer cell apoptosis and cell cycle arrest. In addition, YF479suppresses the activity of cancer cell to form a colony. Metastasis-related cell cultures assay implies YF479finely inhibits tumor cell adhesion, migration and metastasis. Our in vivo studies also verify the efficacy of YF479in tumor growth, metastasis and recurrence, providing a strong rationale for YF479as a novel promising antitumor agent in breast cancer.Taken together, we identify two small molecular compounds with breast cancer inhibitory potency, which provides a theoretical basis and guidance for breast cancer drug development.