| Breast cancer is the second leading cause of cancer death among women in the United States and will result in an estimated 40,480 deaths in 2008, according to the National Cancer Institute (NCI’s SEER Cancer Statistics Review). Three major subtypes of breast cancer (basal-like, HER2+/ER-, and luminal) that have contrary prognosis have been identified by gene expression studies. Comparing two hormone receptor—negative subtypes (basal-like and HER2+/ER-) with the hormone receptor—high luminal group, these two subtypes of breast cancer patients are associated with aggressive disease progression and poor clinical outcome. Thus, we are interested in developing new regimens against hormone receptor-negative breast cancers with the intention of extending survival of patients.;The efficacy and mechanism of two novel small molecules (OSU-03012 and OSU-HDAC42) in against triple-negative and HER2/neu-positive breast cancers were investigated in this thesis. First, we demonstrated that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen by lowering the threshold for tamoxifen’s ER-independent pro-apoptotic effect both in vitro and in vivo. Thus, this experimental regimen could benefit the triple-negative patients who have limited choices in treatment. Second, we identified that HER degradation effect of celecoxib derivatives is through autophagy pathway evidenced by MDC staining and LAMP-2 staining. The role for drug-induced autophagic down-regulation of HER2 in mediating the antiproliferative effects of these compounds in cancer cells was supported by the attenuation of anti-proliferation effect in autophagy inhibitor co-treated cells. Since the mechanistic study suggests that hsp90 is the main target for OSU-03012-induced HER2 down-regulation, a fluorescent polarization assay was established to find more potent compounds from existing OSU-03012 library. Both biochemical assays and computer simulation support T1A-10 and T3-1 as better candidates for developing new generation hsp90 inhibitors. Third, we investigated the effects of various HDAC inhibitors toward the regulation of HER2 and ERα expression and cell viability in different types of breast cancer cells. Our data show that OSU-HDAC42, a novel phenylbutyrate-derived HDAC inhibitor, exerts a more potent suppressive effect on the expression levels of Hsp90 client proteins (HER2, ERα and Akt) than suberoylanilide hydroxamic acid (SAHA; vorinostat) and MS-275, as well as anti-proliferation activity in various cell line. |
