Differential expression of steroid receptors, hsp27, and pS2 in a series of drug resistant human breast tumor cell lines derived following exposure to antitumor drugs or to fractionated X-irradiation.
This study examined whether levels of estrogen receptor (ER), progesterone receptor (PR), and expression of estrogen regulated pS2 and/or heat shock protein (hsp) 27 were associated with drug resistance in a series of MCF-7 sublines expressing modest (i.e. 3- to 14-fold), yet clinically relevant, levels of resistance to vincristine (VCR). These sublines were variously derived following pulsed exposures to VCR, to fractionated X-irradiation, or to alternating drug and X-ray treatments. This selection procedure more closely reflects the clinical treatment of breast tumors than the use of continuous drug exposures. The drug-selected sublines exhibited the classical multidrug resistance phenotype (MDR) characterized by cross-resistance to vinblastine (VLB), etoposide (VP-16), and Adriamycin (ADR), overexpression of P-glycoprotein (Pgp), impaired accumulation of [3H]-VCR and of Rhodamine-123 (Rh 123), and altered activities of certain drug detoxification enzymes. This classic MDR phenotype was associated with a lack of mitogenic response to estrogen or antiestrogen, related to loss of detectable ER and PR; consistent with these data, neither pS2 nor hsp27 expression was detectable. In contrast, X-ray-pretreated VCR-resistant cells (MCF/DXR-10) cells exhibited a distinctive resistance phenotype proving cross-resistant to VLB and VP-16 but not to ADR, and Pgp overexpression was not detectable. Furthermore, these VCR-resistant DXR-10 cells retained parental levels of ER and PR, exhibited sensitivity to estrogen and 4-hydroxytamoxifen, and expressed detectable levels of pS2 and hsp27. Comparable characteristics to these MCF-7/DXR-10 cells were also identified in a similarly-derived X-ray-pretreated VCR-resistant subline of the ZR-75-1 human breast tumor cell line. These data therefore indicate that functional ER are frequently, but not invariably, modified in tumor cells which express resistance to multiple drugs.
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, England.
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Whelan
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Hill
D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology*; D010641:Phenotype; D011506:Proteins; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology*; D011980:Receptors, Progesterone / Q000502:physiology*; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D025521:Tumor Suppressor Proteins; D014750:Vincristine / Q000494:pharmacology; D014965:X-Rays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004965:Estrogen Antagonists; D004967:Estrogens; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D014750:Vincristine; D004317:Doxorubicin