Dexamethasone down-regulates ABCG2 expression levels in breast cancer cells.
The breast cancer resistance protein ABCG2 effluxes a variety of drugs and is believed to play an important role in multidrug resistance to chemotherapy. We show here for the first time that dexamethasone (DEX) and progesterone (PROG) are able to strongly inhibit ABCG2 expression in progesterone receptor (PR)-positive MCF7 and PR-negative MDA-MB-231 breast cells. In contrast, in the latter cells stably-transfected with progesterone receptor isoforms A and B, ABCG2 expression was strongly up-regulated by DEX and PROG. In addition, two other ligands of Pregnane X Receptor (PXR) and/or Glucocorticoid Receptor (GR) were also able to down-regulate ABCG2 expression in PXR- and GR-positive MCF7 cells. ABCG2 expression regulation by DEX likely resulted from the activation of PR-, PXR-, and/or GR-signaling pathways. ABCG2 expression inhibition by DEX was associated with increased sensitivity to mitoxantrone, a known ABCG2 substrate. The findings suggest that DEX may be useful in improving drug efficacy under certain conditions.
Honorat
Mylène
M
Université de Lyon, Lyon1, Lyon, F-69008, France.
Mesnier
Aurélia
A
Di Pietro
Attilio
A
Lin
Valérie
V
Cohen
Pascale
P
Dumontet
Charles
C
Payen
Léa
L
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077297:Pregnane X Receptor; D011374:Progesterone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D000077297:Pregnane X Receptor; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D015735:Mifepristone; D011374:Progesterone; D003907:Dexamethasone; D008942:Mitoxantrone