The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer.
The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer.
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DOI：
10.1126/sciadv.1601737
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发表时间：
2016-10
期刊：
影响因子：
13.6
通讯作者：
Harris RS
中科院分区：
文献类型：
--
作者：
Law EK;Sieuwerts AM;LaPara K;Leonard B;Starrett GJ;Molan AM;Temiz NA;Vogel RI;Meijer-van Gelder ME;Sweep FC;Span PN;Foekens JA;Martens JW;Yee D;Harris RS
一种抗病毒的酶促进了乳腺癌的耐药性。乳腺肿瘤通常表现出极端的遗传异质性，其特征是数百条粗大的染色体异常和数万条体细胞突变。肿瘤的进化被认为是持续的，并受到多种诱变过程的驱动。一个主要悬而未决的问题是，原发肿瘤是否存在治疗耐药的预先存在的突变，或者是否有必要进行额外的DNA损伤和突变。耐药性是衡量肿瘤进化性的关键指标。如果耐药突变在原发肿瘤出现时就已经存在，那么预期的治疗很可能失败。然而，如果耐药性不是预先存在的，那么正在进行的突变过程仍然有可能破坏治疗效果。抗病毒酶APOBEC3B(载脂蛋白B mRNA编辑酶，催化多肽样3B)优先脱氨基DNA C-to-U，导致在乳腺肿瘤中常见的标志性C-to-T和C-to-G突变。我们使用临床数据和异种移植实验来询问APOBEC3B是否有助于正在进行的乳腺肿瘤演变和对选择性雌激素受体调节剂他莫昔芬的耐药性。首先，雌激素受体阳性(ER+)乳腺肿瘤的APOBEC3B水平与他莫昔芬治疗转移性ER+疾病的临床疗效呈负相关。其次，在小鼠异种移植实验中，ER+乳腺癌细胞株中APOBEC3B的缺失会导致三苯氧胺反应延长。第三，APOBEC3B的过表达加速了小鼠异种移植实验中他莫昔芬耐药性的发展，其机制需要酶的催化活性。这些研究结合起来表明，APOBEC3B促进乳腺癌的耐药性，抑制APOBEC3B依赖的肿瘤进化可能是提高靶向癌症治疗效果的有效策略。
An antiviral enzyme promotes drug resistance in breast cancer. Breast tumors often display extreme genetic heterogeneity characterized by hundreds of gross chromosomal aberrations and tens of thousands of somatic mutations. Tumor evolution is thought to be ongoing and driven by multiple mutagenic processes. A major outstanding question is whether primary tumors have preexisting mutations for therapy resistance or whether additional DNA damage and mutagenesis are necessary. Drug resistance is a key measure of tumor evolvability. If a resistance mutation preexists at the time of primary tumor presentation, then the intended therapy is likely to fail. However, if resistance does not preexist, then ongoing mutational processes still have the potential to undermine therapeutic efficacy. The antiviral enzyme APOBEC3B (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3B) preferentially deaminates DNA C-to-U, which results in signature C-to-T and C-to-G mutations commonly observed in breast tumors. We use clinical data and xenograft experiments to ask whether APOBEC3B contributes to ongoing breast tumor evolution and resistance to the selective estrogen receptor modulator, tamoxifen. First, APOBEC3B levels in primary estrogen receptor–positive (ER+) breast tumors inversely correlate with the clinical benefit of tamoxifen in the treatment of metastatic ER+ disease. Second, APOBEC3B depletion in an ER+ breast cancer cell line results in prolonged tamoxifen responses in murine xenograft experiments. Third, APOBEC3B overexpression accelerates the development of tamoxifen resistance in murine xenograft experiments by a mechanism that requires the enzyme’s catalytic activity. These studies combine to indicate that APOBEC3B promotes drug resistance in breast cancer and that inhibiting APOBEC3B-dependent tumor evolvability may be an effective strategy to improve efficacies of targeted cancer therapies.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
168.9
作者：
Davies, Christina;Pan, Hongchao;Godwin, Jon;Gray, Richard;Arriagada, Rodrigo;Raina, Vinod;Abraham, Mirta;Medeiros Alencar, Victor Hugo;Badran, Atef;Bonfill, Xavier;Bradbury, Joan;Clarke, Michael;Collins, Rory;Davis, Susan R.;Delmestri, Antonella;Forbes, John F.;Haddad, Peiman;Hou, Ming-Feng;Inbar, Moshe;Khaled, Hussein;Kielanowska, Joanna;Kwan, Wing-Hong;Mathew, Beela S.;Mittra, Indraneel;Mueller, Bettina;Nicolucci, Antonio;Peralta, Octavio;Pernas, Fany;Petruzelka, Lubos;Pienkowski, Tadeusz;Radhika, Ramachandran;Rajan, Balakrishnan;Rubach, Maryna T.;Tort, Sera;Urrutia, Gerard;Valentini, Miriam;Wang, Yaochen;Peto, Richard
通讯作者：
Peto, Richard
DOI：
10.1126/science.1253462
发表时间：
2014-10-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
de Bruin EC;McGranahan N;Mitter R;Salm M;Wedge DC;Yates L;Jamal-Hanjani M;Shafi S;Murugaesu N;Rowan AJ;Grönroos E;Muhammad MA;Horswell S;Gerlinger M;Varela I;Jones D;Marshall J;Voet T;Van Loo P;Rassl DM;Rintoul RC;Janes SM;Lee SM;Forster M;Ahmad T;Lawrence D;Falzon M;Capitanio A;Harkins TT;Lee CC;Tom W;Teefe E;Chen SC;Begum S;Rabinowitz A;Phillimore B;Spencer-Dene B;Stamp G;Szallasi Z;Matthews N;Stewart A;Campbell P;Swanton C
通讯作者：
Swanton C
影响因子：
11.1
作者：
Kemper K;Krijgsman O;Cornelissen-Steijger P;Shahrabi A;Weeber F;Song JY;Kuilman T;Vis DJ;Wessels LF;Voest EE;Schumacher TN;Blank CU;Adams DJ;Haanen JB;Peeper DS
通讯作者：
Peeper DS
影响因子：
82.9
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
通讯作者：
Engelman JA