Montecchia M F, Molinolo A, Lanari C
Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Cientificas y Técnicas, Buenos Aires, Argentina.
Breast Cancer Res Treat. 1999 Mar;54(2):93-9. doi: 10.1023/a:1006177619192.
From mouse mammary progestin-dependent (PD) adenocarcinomas induced with medroxyprogesterone acetate (MPA) we developed several in vivo lines that are maintained by subcutaneous syngeneic passages in MPA-treated mice and express estrogen (ER) and progesterone receptors (PR). Although most lines remained PD, with time some progestin-independent (PI) variants arose. Both PD and PI tumors regress with estrogen treatment although estrogen-resistant variants may also arise. The object of this paper was to investigate the reversibility of estrogen-resistance and its possible relation with hormone receptor down-regulation. Tumor regression was induced in a progestin-independent tumor line (BET) by treatment with a 5 mg 17beta-estradiol (E2) silastic pellet. One of the tumors started to grow disclosing an estrogen-resistant pattern of growth. This tumor line (BET-R) was transplanted into E2-treated and untreated animals (n = 4-6), selecting for the next passage tumors growing in treated animals. Seven new sublines were obtained at different passages by selecting for the next passage the tumors that had grown in untreated mice (BET-Ra-BET-Rg), until no tumors grew in E2-treated mice. ER and PR were measured by a ligand-binding, dextran-coated charcoal method using a single saturating point. From the seven sublines initiated, the first four proved to be reversible after 3-6 generation transplantation and the last three did not revert. A difference in PR expression between BET and BET-R (p < 0.05) was registered, but it did not correlate with the specific hormone behavior since two reverted lines had a pattern similar to that of BET and the other two were similar to BET-R. The expression of PR was higher in E2-treated mice (p < 0.05) and highly variable in the parental line. This led us to study the expression of PR at different stages of the estrous cycle. Higher levels of PR were observed in proestrous, estrous, and metestrous (p < 0.05) than in diestrous, and undetectable levels were found in ovariectomized mice. No differences in ER expression were detected during the estrous cycle. It can be concluded that under certain experimental conditions, estrogen-resistance is a reversible phenomenon. The experimental manipulation of hormone resistance may help develop strategies to modify the response to anti-hormones in humans.
我们从用醋酸甲羟孕酮（MPA）诱导产生的小鼠乳腺孕激素依赖性（PD）腺癌中，培育出了多个体内细胞系，这些细胞系通过在经MPA处理的小鼠中进行皮下同基因传代来维持，并表达雌激素（ER）和孕激素受体（PR）。尽管大多数细胞系仍为孕激素依赖性，但随着时间推移，出现了一些孕激素非依赖性（PI）变体。孕激素依赖性和非依赖性肿瘤在雌激素治疗后都会消退，不过也可能出现雌激素抵抗性变体。本文的目的是研究雌激素抵抗性的可逆性及其与激素受体下调的可能关系。通过植入含5 mg 17β-雌二醇（E2）的硅橡胶小丸对一个孕激素非依赖性肿瘤细胞系（BET）进行治疗，诱导肿瘤消退。其中一个肿瘤开始生长，呈现出雌激素抵抗性生长模式。将这个肿瘤细胞系（BET-R）移植到经E2处理和未处理的动物体内（n = 4 - 6），为下一次传代选择在经处理动物体内生长的肿瘤。通过为下一次传代选择在未处理小鼠体内生长的肿瘤（BET-Ra - BET-Rg），在不同传代时获得了7个新的亚系，直到在经E2处理的小鼠中不再有肿瘤生长。采用单饱和点配体结合葡聚糖包被活性炭法测量ER和PR。从起始的7个亚系来看，前4个在3 - 6代移植后被证明是可逆的，后3个没有恢复。记录到BET和BET-R之间PR表达存在差异（p < 0.05），但这与特定激素行为无关，因为两个恢复的细胞系具有与BET相似的模式，另外两个与BET-R相似。PR在经E2处理的小鼠中表达较高（p < 0.05），在亲代细胞系中高度可变。这促使我们研究发情周期不同阶段PR的表达。在动情前期、动情期和动情后期观察到PR水平高于间情期（p < 0.05），在去卵巢小鼠中未检测到PR水平。在发情周期中未检测到ER表达的差异。可以得出结论，在某些实验条件下，雌激素抵抗性是一种可逆现象。对激素抵抗性的实验操作可能有助于制定策略来改变人类对抗激素的反应。
