Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation.
Mechanisms of estrogen-independent breast cancer growth driven by low estrogen concentrations are unique versus complete estrogen deprivation.
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DOI：
10.1007/s10549-012-2032-6
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发表时间：
2012-08
影响因子：
3.8
通讯作者：
Rae, James M.
中科院分区：
文献类型：
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作者：
Sikora, Matthew J.;Strumba, Viktoriya;Lippman, Marc E.;Johnson, Michael D.;Rae, James M.
尽管芳香酶抑制剂（AIs）在治疗雌激素受体阳性乳腺癌中取得了成功，但15- 20%接受辅助AIs的患者将在治疗开始后5-10年内复发。乳腺癌细胞的长期雌激素剥夺（LTED）模拟AI诱导的雌激素耗竭，以剖析AI抵抗的机制。然而，我们假设接受AI治疗的一部分患者可能会维持低循环雌激素浓度，从而影响内分泌抵抗的发展。我们扩展了已建立的LTED模型，以解释AI治疗期间雌激素合成的不完全抑制。MCF-7细胞在添加有规定浓度的17β-雌二醇（E2）或雌激素雄激素代谢物5α-雄甾烷-3 β，17 β-二醇（3βAdiol）（一种内源性选择性雌激素受体调节剂）的炭脱血清培养基中生长。在诱导10%或90%最大增殖（分别为EC 10和EC 90）或雌激素剥夺的E2或3βAdiol浓度下选择细胞。在选择期间，通过评估在不存在或存在E2或3βAdiol的情况下的细胞生长来评价雌激素非依赖性。在>7个月的选择之后，在雌激素剥夺的细胞和EC 10选择的细胞中发展了雌激素非依赖性。功能分析表明，雌激素剥夺和EC 10选择的细胞通过独特的机制，ERα独立和依赖，分别发展雌激素依赖性。雌激素非依赖性增殖的EC 10-选择的细胞可以被阻断激酶抑制剂。然而，这些细胞在低类固醇浓度存在下对激酶抑制具有抗性。这些数据表明，进一步了解AI治疗复发患者的总雌激素环境对于有效治疗内分泌抵抗性疾病是必要的。
Despite the success of the aromatase inhibitors (AIs) in treating estrogen receptor positive breast cancer, 15–20 % of patients receiving adjuvant AIs will relapse within 5–10 years of treatment initiation. Long-term estrogen deprivation (LTED) of breast cancer cells in culture mimics AI-induced estrogen depletion to dissect mechanisms of AI resistance. However, we hypothesized that a subset of patients receiving AI therapy may maintain low circulating concentrations of estrogens that influence the development of endocrine resistance. We expanded established LTED models to account for incomplete suppression of estrogen synthesis during AI therapy. MCF-7 cells were grown in medium with charcoal-stripped serum supplemented with defined concentrations of 17β-estradiol (E2) or the estrogenic androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol), an endogenous selective estrogen receptor modulator. Cells were selected in concentrations of E2 or 3βAdiol that induce 10 or 90 percent of maximal proliferation (EC10 and EC90, respectively), or estrogen deprived. Estrogen independence was evaluated during selection by assessing cell growth in the absence or presence of E2 or 3βAdiol. Following >7 months of selection, estrogen independence developed in estrogen-deprived cells and EC10-selected cells. Functional analyses demonstrated that estrogen-deprived and EC10-selected cells developed estrogen independence via unique mechanisms, ERα-independent and dependent, respectively. Estrogen-independent proliferation in EC10-selected cells could be blocked by kinase inhibitors. However, these cells were resistant to kinase inhibition in the presence of low steroid concentrations. These data demonstrate that further understanding of the total estrogen environment in patients on AI therapy who experience recurrence is necessary to effectively treat endocrine-resistant disease.
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影响因子：
--
作者：
DuSell, Carolyn D.;Umetani, Michihisa;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
45.3
作者：
Dixon, J. Michael;Renshaw, Lorna;Dowsett, Mitch
通讯作者：
Dowsett, Mitch
影响因子：
45.3
作者：
Partridge, Ann H.;LaFountain, Andrea;Asnis-Alibozek, Aviva
通讯作者：
Asnis-Alibozek, Aviva
影响因子：
3.8
作者：
Gallicchio, Lisa;MacDonald, Ryan;Helzlsouer, Kathy J.
通讯作者：
Helzlsouer, Kathy J.
影响因子：
45.3
作者：
Dowsett, Mitch;Cuzick, Jack;Peto, Richard
通讯作者：
Peto, Richard