Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models.
Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models.
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DOI：
10.1038/s41523-022-00397-y
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发表时间：
2022-03-10
影响因子：
5.9
通讯作者：
Speers CW
中科院分区：
文献类型：
--
作者：
Michmerhuizen AR;Lerner LM;Pesch AM;Ward C;Schwartz R;Wilder-Romans K;Liu M;Nino C;Jungles K;Azaria R;Jelley A;Zambrana Garcia N;Harold A;Zhang A;Wharram B;Hayes DF;Rae JM;Pierce LJ;Speers CW
内分泌治疗（ET）是雌激素受体阳性（ER +）乳腺癌的有效一线治疗方法。虽然电离辐射（RT）和ET都被用于治疗ER+乳腺癌，但最有效的治疗顺序和ET对肿瘤放射致敏的影响尚不清楚。在这里，我们试图了解抑制雌激素受体（ER）信号传导联合RT对多种临床前ER+乳腺癌模型的影响。在不同的治疗前和治疗后条件下进行克隆生存试验，以评估雌二醇、雌激素剥夺、他莫昔芬、氟维司汀或AZD9496对ER+乳腺癌细胞系的放射增敏作用。雌激素刺激具有辐射防护作用（辐射增强比[rER]: 0.51-0.82）。相反，在放疗前1小时给予ER抑制或雌激素耗竭会使ER+ MCF-7和T47D细胞增敏（他莫昔芬rER: 1.50-1.60，氟维司汀rER: 1.76-2.81, AZD9496 rER: 1.33-1.48，雌激素耗竭rER: 1.47-1.51）。联合治疗导致双链DNA （dsDNA）断裂增加，这是由于抑制了非同源末端连接介导的dsDNA断裂修复，而对同源重组没有影响。他莫昔芬或氟维司汀联合RT治疗也增加了衰老细胞的数量，但不影响细胞凋亡或细胞周期分布。在MCF-7异种移植模型中，他莫昔芬和RT同时治疗具有协同作用，导致肿瘤体积显著减少，肿瘤翻倍时间延迟，且无明显毒性。这些发现提供了临床前证据，表明ET和RT同时治疗可能是有效的放射增敏策略。
Endocrine therapy (ET) is an effective first-line therapy for women with estrogen receptor-positive (ER + ) breast cancers. While both ionizing radiation (RT) and ET are used for the treatment of women with ER+ breast cancer, the most effective sequencing of therapy and the effect of ET on tumor radiosensitization remains unclear. Here we sought to understand the effects of inhibiting estrogen receptor (ER) signaling in combination with RT in multiple preclinical ER+ breast cancer models. Clonogenic survival assays were performed using variable pre- and post-treatment conditions to assess radiosensitization with estradiol, estrogen deprivation, tamoxifen, fulvestrant, or AZD9496 in ER+ breast cancer cell lines. Estrogen stimulation was radioprotective (radiation enhancement ratios [rER]: 0.51–0.82). Conversely, when given one hour prior to RT, ER inhibition or estrogen depletion radiosensitized ER+ MCF-7 and T47D cells (tamoxifen rER: 1.50–1.60, fulvestrant rER: 1.76–2.81, AZD9496 rER: 1.33–1.48, estrogen depletion rER: 1.47–1.51). Combination treatment resulted in an increase in double-strand DNA (dsDNA) breaks as a result of inhibition of non-homologous end joining-mediated dsDNA break repair with no effect on homologous recombination. Treatment with tamoxifen or fulvestrant in combination with RT also increased the number of senescent cells but did not affect apoptosis or cell cycle distribution. Using an MCF-7 xenograft model, concurrent treatment with tamoxifen and RT was synergistic and resulted in a significant decrease in tumor volume and a delay in time to tumor doubling without significant toxicity. These findings provide preclinical evidence that concurrent treatment with ET and RT may be an effective radiosensitization strategy.
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DOI：
10.1186/bcr969
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Azria D;Larbouret C;Cunat S;Ozsahin M;Gourgou S;Martineau P;Evans DB;Romieu G;Pujol P;Pèlegrin A
通讯作者：
Pèlegrin A
影响因子：
--
作者：
Liu Z;Wang L;Yang J;Bandyopadhyay A;Kaklamani V;Wang S;Sun LZ
通讯作者：
Sun LZ
影响因子：
0.6
作者：
Pellicciaro M;Granai AV;Marchese G;Materazzo M;Cotesta M;Santori F;Giacobbi E;Servadei F;Grelli S;Perretta T;Meucci R;Pistolese CA;Vanni G
通讯作者：
Vanni G
影响因子：
3.4
作者：
Alotaibi M;Sharma K;Saleh T;Povirk LF;Hendrickson EA;Gewirtz DA
通讯作者：
Gewirtz DA
影响因子：
45.3
作者：
Kyndi, Marianne;Sorensen, Flemming B.;Overgaard, Jens
通讯作者：
Overgaard, Jens