Johnston S R, Saccani-Jotti G, Smith I E, Salter J, Newby J, Coppen M, Ebbs S R, Dowsett M
Academic Department of Biochemistry, Royal Marsden Hospital, London, England.
Cancer Res. 1995 Aug 1;55(15):3331-8.
Changes in estrogen receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. ER expression was measured by an immunohistochemical assay, validated for use in tamoxifen-treated tumors against a biochemical enzyme immunoassay, in 72 paired biopsies taken before treatment and at progression or relapse on tamoxifen. Progesterone receptor (PgR) and pS2 gene expression were also measured immunohistochemically as an indicator of ER function. Overall the frequency of ER expression was reduced from 37 of 72 (51%) pretamoxifen to 21 of 72 (29%) at progression or relapse, with a significant reduction in the quantitative level of ER (P < 0.0001; Wilcoxon signed rank sum test). Tumors treated with primary tamoxifen that responded but then developed acquired resistance frequently remained ER positive (ER+) at relapse: 16 of 18 (89%) were ER+ pretamoxifen (75% of these expressed either PgR or pS2) and 11 of 18 (61%) were ER+ at relapse (82% continued to express PgR or pS2). In contrast, only 3 of 20 (15%) tumors that progressed on primary tamoxifen with de novo resistance were ER+ pretamoxifen, and all tumors were ER- at progression. At progression, 6 of 20 (30%) of these tumors expressed high levels of PgR (mean H-score, 98) and/or pS2 (mean, 50% cells positive), despite being ER-. In tumors that recurred during adjuvant tamoxifen therapy, including locoregional and metastatic lesions, ER expression was significantly reduced from 18 of 34 (53%) in the original primary tumor to 10 of 34 (29%) at relapse (P = 0.002). PgR expression was likewise significantly reduced in this group (P = 0.001). This study confirms that expression of a functional ER in breast cancer is a strong predictor for primary response to tamoxifen. Although ER was reduced in tamoxifen-resistant tumors overall, the development of acquired resistance was associated with maintained ER expression and function in many tumors, whereas de novo resistance remained related to lack of ER expression. Recurrence during adjuvant tamoxifen was associated with development of an ER/PgR-negative phenotype in some tumors. These data imply that separate mechanisms of resistance may occur in these different clinical subgroups.
雌激素受体（ER）表达和功能的变化可能解释乳腺癌中他莫昔芬耐药的发生。通过免疫组织化学检测法测定ER表达，并针对一种生化酶免疫测定法进行验证，该免疫组织化学检测法用于他莫昔芬治疗的肿瘤，检测了72例配对活检标本，分别在治疗前以及他莫昔芬治疗进展或复发时采集。还通过免疫组织化学方法检测了孕激素受体（PgR）和pS2基因表达，作为ER功能的指标。总体而言，ER表达频率从他莫昔芬治疗前72例中的37例（51%）降至进展或复发时72例中的21例（29%），ER定量水平显著降低（P < 0.0001；Wilcoxon符号秩和检验）。接受初始他莫昔芬治疗有反应但随后出现获得性耐药的肿瘤在复发时通常仍为ER阳性（ER+）：18例中有16例（89%）在他莫昔芬治疗前为ER+（其中75%表达PgR或pS2），18例中有11例（61%）在复发时为ER+（82%继续表达PgR或pS2）。相比之下，初始他莫昔芬治疗进展且为原发性耐药的20例肿瘤中，只有3例（15%）在他莫昔芬治疗前为ER+，且所有肿瘤在进展时均为ER阴性。在进展时，这些肿瘤中有20例中的6例（30%）表达高水平的PgR（平均H评分，98）和/或pS2（平均，50%细胞阳性），尽管为ER阴性。在辅助性他莫昔芬治疗期间复发的肿瘤，包括局部区域和转移性病变，ER表达从原发肿瘤中34例中的18例（53%）显著降至复发时34例中的10例（29%）（P = 0.002）。该组中PgR表达同样显著降低（P = 0.001）。本研究证实，乳腺癌中功能性ER的表达是对他莫昔芬原发性反应的有力预测指标。尽管总体上他莫昔芬耐药肿瘤中的ER减少，但在许多肿瘤中获得性耐药的发生与ER表达和功能的维持有关，而原发性耐药仍与ER表达缺失有关。辅助性他莫昔芬治疗期间的复发在一些肿瘤中与ER/PgR阴性表型的出现有关。这些数据表明，在这些不同的临床亚组中可能发生不同的耐药机制。
