Induction of apoptosis in hormone refractory breast cancer: horizontal modulation is superior to vertical.

Women with estrogen receptor positive (ER+) breast cancer receive treatment with tamoxifen or aromatase inhibitors as adjuvant hormone therapy, but their tumors frequently exhibit de novo or acquired resistance. Current strategies being developed to overcome resistance involve a combination of growth factor pathway inhibitors in addition to hormone therapy. Unfortunately, prolongation of responses with these new approaches is measured only in months.

Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland.

Extensive data suggest that estradiol contributes to the development of breast cancer by acting as a mitogen and exerting direct genotoxic effects after enzymatic conversion to 4-hydroxyestradiol (4-OHE2) via cytochrome P450 1B1 (CYP1B1). The mammary gland, ovary, and uterus all express CYP1B1. Overexpression of this enzyme has been associated with an increased risk of breast cancer and blockade might reduce this carcinogenic effect.

Anticancer effect of (E)-2-hydroxy-3',4,5'-trimethoxystilbene on breast cancer cells by mitochondrial depolarization.

Background: TMS (2,3',4,5'-tetramethoxystilbene), a stilbene analog derived from rhapontigenin, was previously demonstrated to induce apoptosis in hormone-resistant breast cancer cells. Therefore, this study investigated the anticancer effect of a new stilbene analog, HTMS ((E)-2-hydroxy-3',4,5'-trimethoxystilbene), and its mechanism in various breast cancer cell lines.

Materials And Methods: The effect of HTMS on cell proliferation of MDA-MB-231, MCF-7, and LTED cells was evaluated using MTT assays.

Aromatase immunoreactivity is increased in mammographically dense regions of the breast.

Mammographic breast density (MBD) is one of the strongest risk factors for breast cancer. Unfortunately, the biologic basis underlying this association is unknown. This study compared aromatase expression or immunoreactivity (IR) in core biopsies from mammographically dense versus non-dense regions of the breast to examine whether estrogen synthesis in the breast is associated with MBD and one possible mechanism through which MBD may influence breast cancer.

TMS, a chemically modified herbal derivative of resveratrol, induces cell death by targeting Bax.

Breast cancer recurrence after an initial favorable response to treatment is a major concern for patients who receive hormonal therapies. Additional therapies are necessary to extend the time of response, and ideally, these therapies should exhibit minimal toxicity. Our study described herein focuses on a non-toxic pro-apoptotic agent, TMS (2,4,3',5'-tetramethoxystilbene), which belongs to the Resveratrol family of stilbenes.

Mechanisms of resistance to structurally diverse antiestrogens differ under premenopausal and postmenopausal conditions: evidence from in vitro breast cancer cell models.

This study questioned whether the mechanisms of resistance to antiestrogens differ when acquired under premenopausal (Pre-M) vs. postmenopausal (PM) conditions and whether structurally diverse antiestrogens induce adaptation of differing signaling pathways. To address this issue, we conducted systematic studies under Pre-M vs.

Concerted transcriptional regulation by BRCA1 and COBRA1 in breast cancer cells.

Cofactor of BRCA1 (COBRA1) was first identified as a protein that binds to the breast cancer susceptibility gene product BRCA1. COBRA1 modulates estrogen-dependent and independent transcription and suppresses the growth of breast cancer cells. Its expression is significantly reduced in metastatic and recurrent breast cancer, pointing to a tumor suppressor function in breast cancer development.

Development of a high sensitivity, nested Q-PCR assay for mouse and human aromatase.

Measurement of breast tissue estradiol levels could provide a powerful method to predict the risk of developing breast cancer but obtaining sufficient amounts of tissue from women is difficult from a practical standpoint. Assessment of aromatase in ductal lavage fluid or fine needle aspirates from breast might provide a surrogate marker for tissue estrogen levels but highly sensitive methods would be required. These considerations prompted us to develop an ultra-sensitive, "nested" PCR assay for aromatase which is up to one million fold more sensitive than standard PCR methods.

Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing.

Transcriptional activity of nuclear receptors (NRs) is influenced by a large number of coregulators that exert their actions predominantly at the transcription initiation step. Unlike most well-characterized NR coregulators, cofactor of BRCA1 (COBRA1), a subunit of the negative elongation factor (NELF), binds to estrogen receptor alpha (ERalpha) and modulates estrogen-dependent transcription by impeding the movement of RNA polymerase II (RNAPII) during the transcription elongation stage. Here we show that, in addition to ERalpha, COBRA1 also displays various degrees of affinity for several other NRs.

Effects of tetramethoxystilbene on hormone-resistant breast cancer cells: biological and biochemical mechanisms of action.

Secondary resistance to hormonal therapy for breast cancer commonly develops after an initial response to tamoxifen or aromatase inhibitors. Agents to abrogate these adaptive changes would substantially enhance the long-term benefits of hormonal therapy. Our studies with a stilbene derivative called TMS (2,3',4,5'-tetramethoxystilbene) identified unexpected effects with potential utility for treatment of breast tumors secondarily resistant to hormonal therapy.

Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal adenocarcinomas.

Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs.

BRCA1: a locus-specific "liaison" in gene expression and genetic integrity.

Mutations in BRCA1 predominantly lead to elevated risks of breast and ovarian cancers. In contrast to the tissue-specific nature of BRCA1tumors, the normal BRCA1 gene product functions in diverse nuclear events including transcription, DNA repair, and DNA damage checkpoint. Recent findings of physical and functional associations between BRCA1 and the RNA polymerase II (RNAPII)-dependent transcription machinery may shed some light on this longstanding paradox of BRCA1 biology.

Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor.

Estrogen receptor alpha (ERalpha) signaling is paramount for normal mammary gland development and function and the repression of breast cancer. ERalpha function in gene regulation is mediated by a number of coactivators and corepressors, most of which are known to modify chromatin structure and/or influence the assembly of the regulatory complexes at the level of transcription initiation. Here we describe a novel mechanism of attenuating the ERalpha activity.

The C-terminal domains of the RNA polymerase alpha subunits: contact site with Fis and localization during co-activation with CRP at the Escherichia coli proP P2 promoter.

Fis is a versatile transactivator that functions at many different promoters. Fis activates transcription at the RpoS-dependent proP P2 promoter when bound to a site that overlaps the minus sign35 hexamer by a mechanism that requires the C-terminal domain of the alpha subunit of RNA polymerase (alphaCTD). The region on Fis responsible for activating transcription through the alphaCTD has been localized to a short beta-turn near the DNA-binding determinant on one subunit of the Fis homodimer.

Architecture of Fis-activated transcription complexes at the Escherichia coli rrnB P1 and rrnE P1 promoters.

The transcription factor Fis activates the Escherichia coli rRNA promoters rrnB P1 and rrnE P1 by binding to sites centered at -71 and -72, respectively, and interacting with the C-terminal domain of the alpha subunit of RNA polymerase (RNAP alphaCTD). To understand the mechanism of activation by Fis at these promoters, we used oriented alpha-heterodimeric RNAPs and heterodimers of Fis to determine whether one or both subunits of alpha and Fis participate in the alphaCTD-Fis interaction. Our results imply that only one alphaCTD in the alpha dimer and only one activation-proficient subunit in the Fis dimer are required for activation by Fis.

rRNA promoter activity in the fast-growing bacterium Vibrio natriegens.

The bacterium Vibrio natriegens can double with a generation time of less than 10 min (R. G. Eagon, J.