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.
Whelan
R D
RD
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, England.
Hill
B T
BT
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