Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Abstract

Multidrug resistance, the phenomenon by which cells treated with a drug become resistant to the cytotoxic effect of a variety of other structurally and functionally unrelated drugs, is often associated with the expression of P-glycoprotein, an efflux membrane pump coded by the MDR1 (ABCB1) gene. Transcription from MDR1 can start at 2 promoters: a well-characterized downstream promoter and an as yet uncharacterized upstream promoter (USP). We have previously determined that the USP is activated in some drug-resistant cell lines, in primary breast tumors and in metastatic epithelial cells isolated from the lymph nodes of breast cancer patients. In this study, we report the cloning and characterization of the MDR1 USP and studied its association with chemotherapy response in breast cancer patients. Deletion analysis indicated that a nearby endogenous retroviral long terminal repeat is not responsible for promoter activation, and that the region within the first 400 nucleotides upstream from the transcription start point contained all the elements necessary for promoter activity in drug-resistant cells. We identified an element recognized by the transcription factor NF-IL6 (activated upon interleukin-6 exposure) which is necessary for promoter activity in drug-resistant cells and plays a role in the activation of the promoter in response to interleukin-6 in breast cancer MCF-7 cells. Although transcripts from this promoter are associated with translating polyribosomes, their low abundance makes the amount of synthesized P-glycoprotein insufficient to affect the response to first-line chemotherapy in patients with advanced breast cancer. ' 2007 Wiley-Liss, Inc.

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

“…Interestingly, NCI/ADR-RES, multidrug-resistant cells overexpressing the ABC transporter ABCB1 (P-glycoprotein) (Raguz et al, 2008) and prostate PC-3 cells, are the least susceptible of all the cells in the NCI-60 cell panel. As PC-3 cells express also P-glycoprotein (Rao et al, 2005), and considering the molecular structure of GSI1, it is possible that GSI1 will be a substrate of P-glycoprotein (Crivori et al, 2006).…”

ABCB1regulation through LRPPRC is influenced by the methylation status of the GC -100 box in its promoter

“…[35][36][37][38] Although ABCB1 has been identified to have two different promoters, both of them producing the same protein, 39 the downstream promoter is the major promoter in most cells. [40][41][42] The downstream promoter has CpG islands and contains two GC boxes, GC-50 (-56/-45) and GC-100 (-110/-103), for transcriptional regulation by DNA methylation. GC -50 box hypomethylation has been described as a poor prognostic factor in hematological malignancy in patients with or without bone marrow transplantation (BMT), due to ABCB1 upregulation.…”

Az MDR1 gén kromatin szerkezetének tanulmányozása gyógyszerérzékeny és gyógyszerrezisztens humán sejtekben

“…Az MDR1 gén transzkripciója két promótertől iniciálódhat (Ueda, Clark et al 1987). Ez általános jelenség, a humán genomban a gének 18 %-a, többek között az ABCG1, ABCG2, ABCA1 gének is, alternatív promóterekről íródhatnak át (Raguz, Randle et al 2008). Az MDR1 mRNS képződés a legtöbb esetben a downstream promótertől indul.…”

“…Az UPS normál emlősejtek 10 %-ában és az emlőrákos sejtek 70 %-ában aktiválódik. Az UPS-től iniciálódó transzkripció korrelál az emlőtumor metasztázisával (Raguz, Tamburo De Bella et al 2004), annak ellenére, hogy az UPS-től átíródó transzkriptum alacsony mennyiségű és szignifikánsan nem befolyásolja a kemoterápia hatékonyságát (Raguz, Randle et al 2008). Az innen induló transzkripció humán szarkóma sejtekben együtt jár az MDR1 géntől upstream irányban lévő MCFP (mitochondrial carrier family protein) és RUNDC3/RPIB9 (RUN domain containing 3B/Rap2 interacting protein 9) gének expressziójának aktiválódásával (Chen, Wang et al 2005;Raguz, De Bella et al 2005), ami a régió megváltozott kromatin szerkezetével lehet összefüggésben.…”