PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors.
PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors.
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DOI：
10.1186/s13058-021-01387-x
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发表时间：
2021-01-21
期刊：
影响因子：
--
通讯作者：
Pei XH
中科院分区：
文献类型：
--
作者：
Bai F;Liu S;Liu X;Hollern DP;Scott A;Wang C;Zhang L;Fan C;Fu L;Perou CM;Zhu WG;Pei XH
基底细胞样乳腺癌（BLBC）是癌症死亡的主要原因，因为它们具有转移能力并且缺乏有效的治疗方法。超过一半的BLBC具有功能失调的BRCA 1。尽管大多数BRCA 1缺陷型癌症对DNA损伤剂有反应，但耐药性和肿瘤复发仍然是BLBC患者生存结局的挑战。目前迫切需要针对BRCA 1缺陷异常激活的途径的其他疗法。大多数BRCA 1缺陷型BLBC携带功能失调的INK 4-RB通路。因此，我们创建了Brca 1缺失和p16 INK 4A缺失或单独p18 INK 4C缺失的基因工程小鼠，以模拟人类BLBC中INK 4-RB信号传导缺陷。通过使用这些突变小鼠和人类BRCA 1缺陷和熟练的乳腺癌组织和细胞，我们测试了BRCA 1缺陷乳腺癌中是否存在可药物靶点。在p18 INK 4C或p16 INK 4A缺陷小鼠中，Brca 1的杂合子生殖系或上皮特异性缺失激活了Pdgfrβ信号传导，诱导了上皮向间质转化，并导致BLBC。在Brca 1缺陷肿瘤细胞中靶向缺失Pdgfrβ可促进细胞死亡，诱导间质向上皮转化，并抑制肿瘤发生，从而证实了这一作用。重要的是，我们还发现药物抑制Pdgfrβ及其下游靶点Pkcα可抑制Brca 1缺陷型肿瘤的发生和进展，并有效杀死BRCA 1缺陷型癌细胞。我们的工作提供了第一个遗传和生化证据，证明PDGFRβ-PKCα信号被BRCA 1抑制，这将PDGFRβ-PKCα信号作为BRCA 1缺陷乳腺癌的治疗靶点。在线版本包含补充材料，可通过10.1186/s13058-021-01387-x获得。
Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrβ signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrβ in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrβ and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. Our work offers the first genetic and biochemical evidence that PDGFRβ-PKCα signaling is repressed by BRCA1, which establishes PDGFRβ-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers. The online version contains supplementary material available at 10.1186/s13058-021-01387-x.
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影响因子：
15.9
作者：
Jechlinger, Martin;Sommer, Andreas;Gruenert, Stefan
通讯作者：
Gruenert, Stefan
影响因子：
11.2
作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
通讯作者：
Mani SA
影响因子：
3.8
作者：
Forte L;Turdo F;Ghirelli C;Aiello P;Casalini P;Iorio MV;D'Ippolito E;Gasparini P;Agresti R;Belmonte B;Sozzi G;Sfondrini L;Tagliabue E;Campiglio M;Bianchi F
通讯作者：
Bianchi F
影响因子：
11.2
作者：
Hsu YH;Yao J;Chan LC;Wu TJ;Hsu JL;Fang YF;Wei Y;Wu Y;Huang WC;Liu CL;Chang YC;Wang MY;Li CW;Shen J;Chen MK;Sahin AA;Sood A;Mills GB;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM