Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.
Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1.
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由于 BARD1 和 BRCA1 上调，他莫昔芬耐药乳腺癌细胞对 DNA 损伤性化疗具有耐药性
DOI：
10.1038/s41467-018-03951-0
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发表时间：
2018-04-23
影响因子：
16.6
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Zhu Y;Liu Y;Zhang C;Chu J;Wu Y;Li Y;Liu J;Li Q;Li S;Shi Q;Jin L;Zhao J;Yin D;Efroni S;Su F;Yao H;Song E;Liu Q
他莫昔芬耐药是许多ER阳性乳腺癌患者复发的原因。大多数复发患者接受化疗，但其化疗敏感性尚不清楚。在这里，我们报告说，他莫昔芬耐药乳腺癌细胞表达显着更多的BARD 1和BRCA 1，导致耐药的DNA损伤化疗，包括顺铂和阿霉素，但不紫杉醇。Dinaciclib沉默BARD 1或BRCA 1表达或抑制BRCA 1磷酸化可恢复他莫昔芬耐药细胞对顺铂的敏感性。此外，我们发现激活的PI 3 K/AKT通路负责BARD 1和BRCA 1的上调。PI 3 K抑制剂降低了他莫昔芬耐药细胞中BARD 1和BRCA 1的表达，并使它们在体外和体内对顺铂重新敏感。较高的BARD 1和BRCA 1表达与早期乳腺癌患者的预后较差相关，特别是接受放射治疗的患者，这表明PI 3 K抑制剂可能用于逆转ER阳性乳腺癌患者的化疗耐药性和放射耐药性。大多数乳腺癌患者是雌激素受体阳性，因此受益于抑制雌激素产生的治疗;然而，三分之一的他莫昔芬治疗的患者产生耐药性和复发。在这里，作者表明，他莫昔芬耐药细胞对化疗耐药，因为BARD 1和BRCA 1上调。
Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients. Most breast cancer patients are estrogen receptor positive and thus benefit from treatments that inhibit estrogen production; however, one third of tamoxifen-treated patients develops resistance and relapse. Here the authors show that tamoxifen resistant cells are resistant to chemotherapy because of BARD1 and BRCA1 upregulation.
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影响因子：
3.8
作者：
Hiscox S;Baruha B;Smith C;Bellerby R;Goddard L;Jordan N;Poghosyan Z;Nicholson RI;Barrett-Lee P;Gee J
通讯作者：
Gee J
DOI：
10.1093/annonc/mdx036
发表时间：
2017-12-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Cardoso F;Costa A;Senkus E;Aapro M;André F;Barrios CH;Bergh J;Bhattacharyya G;Biganzoli L;Cardoso MJ;Carey L;Corneliussen-James D;Curigliano G;Dieras V;El Saghir N;Eniu A;Fallowfield L;Fenech D;Francis P;Gelmon K;Gennari A;Harbeck N;Hudis C;Kaufman B;Krop I;Mayer M;Meijer H;Mertz S;Ohno S;Pagani O;Papadopoulos E;Peccatori F;Penault-Llorca F;Piccart MJ;Pierga JY;Rugo H;Shockney L;Sledge G;Swain S;Thomssen C;Tutt A;Vorobiof D;Xu B;Norton L;Winer E
通讯作者：
Winer E
影响因子：
64.5
作者：
Joukov, Vladimir;Groen, Aaron C.;Livingston, David M.
通讯作者：
Livingston, David M.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
168.9
作者：
Davies, C.;Godwin, J.;Gray, R.;Clarke, M.;Darby, S.;McGale, P.;Wang, Y. C.;Peto, R.;Pan, H. C.;Cutter, D.;Taylor, C.;Ingle, J.
通讯作者：
Ingle, J.