Prolylcarboxypeptidase promotes IGF1R/HER3 signaling and is a potential target to improve endocrine therapy response in estrogen receptor positive breast cancer.
Prolylcarboxypeptidase promotes IGF1R/HER3 signaling and is a potential target to improve endocrine therapy response in estrogen receptor positive breast cancer.
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DOI：
10.1080/15384047.2022.2142008
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发表时间：
2022-12-31
影响因子：
3.6
通讯作者：
Maki, Carl G.
中科院分区：
文献类型：
--
作者：
Duan, Lei;Calhoun, Sarah J.;Perez, Ricardo E.;Macias, Virgilia;Mir, Fatima;Gattuso, Paolo;Maki, Carl G.
脯氨酰羧肽酶（PRCP）是一种溶酶体丝氨酸蛋白酶，当倒数第二个氨基酸是脯氨酸时，其切割肽底物。先前的研究已经将PRCP与血压和食欲控制联系起来，通过其切割肽底物如血管紧张素II和α-MSH的能力。迄今为止，PRCP在癌症中的潜在作用尚未得到广泛认可。乳腺癌内分泌治疗耐药是一个持久的临床问题，部分介导的异常受体酪氨酸激酶（RTK）信号。我们以前发现PRCP过表达促进雌激素受体阳性（ER+）乳腺癌细胞对4-羟基他莫昔芬（4-OHT）的耐药性。目前，我们测试了PRCP与乳腺癌患者结局和RTK信号传导之间的潜在关联，以及肿瘤对内分泌治疗的反应性。我们发现ER+乳腺肿瘤中PRCP蛋白水平高与乳腺癌患者（包括接受TAM治疗的患者）的预后较差和早期复发相关。我们发现PRCP特异性抑制剂（PRCPi）增强了ER+ PDX肿瘤和MCF 7肿瘤对内昔芬（TAM在小鼠中的活性代谢物）的反应。我们发现PRCP增加了ER+乳腺癌细胞中IGF 1 R/HER 3信号传导和AKT激活，而PRCPi则阻断了这一过程。因此，PRCP是乳腺癌的不良预后标志物，也是改善ER+乳腺癌内分泌治疗的潜在靶点。
Prolylcarboxypeptidase (PRCP) is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. Previous studies have linked PRCP to blood-pressure and appetite control through its ability to cleave peptide substrates such as angiotensin II and α-MSH. A potential role for PRCP in cancer has to date not been widely appreciated. Endocrine therapy resistance in breast cancer is an enduring clinical problem mediated in part by aberrant receptor tyrosine kinase (RTK) signaling. We previously found PRCP overexpression promoted 4-hydroxytamoxifen (4-OHT) resistance in estrogen receptor-positive (ER+) breast cancer cells. Currently, we tested the potential association between PRCP with breast cancer patient outcome and RTK signaling, and tumor responsiveness to endocrine therapy. We found high PRCP protein levels in ER+ breast tumors associates with worse outcome and earlier recurrence in breast cancer patients, including patients treated with TAM. We found a PRCP specific inhibitor (PRCPi) enhanced the response of ER+ PDX tumors and MCF7 tumors to endoxifen, an active metabolite of TAM in mice. We found PRCP increased IGF1R/HER3 signaling and AKT activation in ER+ breast cancer cells that was blocked by PRCPi. Thus, PRCP is an adverse prognostic marker in breast cancer and a potential target to improve endocrine therapy in ER+ breast cancers.
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影响因子：
11.2
作者：
Miller TW;Pérez-Torres M;Narasanna A;Guix M;Stål O;Pérez-Tenorio G;Gonzalez-Angulo AM;Hennessy BT;Mills GB;Kennedy JP;Lindsley CW;Arteaga CL
通讯作者：
Arteaga CL
DOI：
10.1001/jama.2011.593
发表时间：
2011-05-11
期刊：
JAMA
影响因子：
--
作者：
Hatzis C;Pusztai L;Valero V;Booser DJ;Esserman L;Lluch A;Vidaurre T;Holmes F;Souchon E;Wang H;Martin M;Cotrina J;Gomez H;Hubbard R;Chacón JI;Ferrer-Lozano J;Dyer R;Buxton M;Gong Y;Wu Y;Ibrahim N;Andreopoulou E;Ueno NT;Hunt K;Yang W;Nazario A;DeMichele A;O'Shaughnessy J;Hortobagyi GN;Symmans WF
通讯作者：
Symmans WF
影响因子：
50.5
作者：
deGraffenried, LA;Friedrichs, WE;Hidalgo, M
通讯作者：
Hidalgo, M
影响因子：
3.8
作者：
Itoh, Mitsuya;Iwamoto, Takayuki;Pusztai, Lajos
通讯作者：
Pusztai, Lajos
DOI：
10.1186/bcr2883
发表时间：
2011-05-19
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Zhang Y;Moerkens M;Ramaiahgari S;de Bont H;Price L;Meerman J;van de Water B
通讯作者：
van de Water B