Abstract 2042: TOB1 promotes cell survival in estrogen-independent estrogen receptor-positive breast cancer.

Abstract

Antiestrogens are the most widely administered endocrine agents for the treatment of estrogen receptor (ER)-expressing breast cancers, such as tamoxifen, fulvestrant and aromatase inhibitor. However, most initially responsive breast tumors acquire resistance and become estrogen-independent. To find potential therapeutic target(s) against drug resistance, we performed siRNA library screening studies to identify cell survival determinants in estrogen independent cell lines from 631 ER network related genes. LCC1 and LCC9 cells, derivatives of MCF-7, are estrogen-independent. LCC1 cells are sensitive to fulvestrant and tamoxifen. LCC9 cells are resistant to fulvestrant and cross-resistant to tamoxifen. A number of genes selectively support the survival of estrogen-independent tumor cells, including TOB1 (Transducer of ErbB2). TOB1 gene knockdown significantly inhibited (>50%) estrogen-independent cell growth in LCC1 and LCC9 cells, but had much less effect on the survival of MCF-7 cells (10%). These cell lines have similar levels of Tob1 protein. TOB1 knockdown did not cause apoptosis or autophagy. DNA replication was reduced and G1 to S phase transition was blocked by TOB1 knockdown in the estrogen-independent cell lines. Next, we studied cell-signaling pathways that regulate cell cycle transition. Cyclin D1 was upregulated and activated by TOB1 knockdown in estrogen-independent cells, but not in MCF-7 cells. Therefore, cyclin D1 might be involved in G1/S transition blockage induced by Tob1 inhibition. TOB1 knockdown also activated cell cycle checkpoint kinase 2 (Chk2) and induced DNA damage. Our data demonstrated that Tob1 promotes cell survival after ER+ breast cancer cells acquire estrogen-independence, which might be mediated by cyclin D1. Citation Format: Yong-Wei Zhang, Rochelle Nasto, Robert Clarke, Louis M. Weiner. TOB1 promotes cell survival in estrogen-independent estrogen receptor-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2013-2042

Aglaiabbrevins A–D, New Prenylated Bibenzyls from the Leaves of <i>Aglaia abbreviata</i> with Potent PTP1B Inhibitory Activity

“…The EtOAc-soluble portion of the EtOH extract was repeatedly subjected to silica gel and Sephadex LH-20 column chromatography, followed by reversed-phase semipreparative HPLC purification, providing four new prenylated bibenzyls (2, 4-6) and two known analogues (7,8). By comparing their observed and reported spectroscopic data, the known bibenzyls were identified as 3,5-dihydroxy-2-[3,7-dimethyl-2(E), 6octadienyl] bibenzyl (7) 16) and 3,5-dihydroxy-2-(3-methyl-2-butenyl) bibenzyl (8).…”

“…500-1600 m altitude, is widely distributed throughout southwestern China. 4) Members of the genus Aglaia have been studied extensively, resulting in the isolation of many types of interesting secondary metabolites, particularly of various triterpenoids (e.g., cycloartanes, dammaranes, tirucallanes) and flavaglines (e.g., cyclopenta [b] [8][9][10] In an ongoing research for biologically active substances from various natural sources, 11-15) the plant A. abbreviata attracted our attention because the ethyl acetate (EtOAc) extract of the leaves of this plant showed inhibitory activity against PTP1B with an 65.2% inhibition at the concentration of 20 µg/mL. As a result, four new (aglaiabbrevins A-D, 2, 4-6) and two known (7, 8) prenylated bibenzyls were isolated (Fig.…”

“…[6][7][8][9][10] Previous phytochemical investigations of A. abbreviata have led to the isolation and characterization of a bisamide, 6) four pregnane steroids, 7) three nortriterpenoids, 8) and five dammarane triterpenoids. [8][9][10] In an ongoing research for biologically active substances from various natural sources, [11][12][13][14][15] the plant A. abbreviata attracted our attention because the ethyl acetate (EtOAc) extract of the leaves of this plant showed inhibitory activity against PTP1B with an 65.2% inhibition at the concentration of 20 µg/mL. As a result, four new (aglaiabbrevins A-D, 2, 4-6) and two known (7, 8) prenylated bibenzyls were isolated (Fig.…”

Cytotoxicity and Structure Activity Relationship of Dammarane-Type Triterpenoids from the Bark of Aglaia elliptica against P-388 Murine Leukemia Cells

“…3,4 The plant is used in Indonesian folk medicine for the treatment of fever, diarrhea, contused wound, coughs and skin diseases. 4 Previous phytochemical studies on Aglaia plants reported the presence of rocaglamide, 5,6,7 bisamides, 8,9 sesquiterpenoids, 10,11 diterpenoids, 12,13 dammaranetype triterpenoids, [14][15][16] cycloartane-type triterpenoids, 17,18 and apotirucallane triterpenoids. 19,20 Although secondary metabolites of other Aglaia species have been investigated previously, the chemical composition of A. ellipticais yet to be reported.…”