Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers.
Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers.
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DOI：
10.1007/s10549-010-1078-6
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发表时间：
2011-07
影响因子：
3.8
通讯作者：
Sartorius, Carol A.
中科院分区：
文献类型：
--
作者：
Kabos, Peter;Haughian, James M.;Wang, Xinshuo;Dye, Wendy W.;Finlayson, Christina;Elias, Anthony;Horwitz, Kathryn B.;Sartorius, Carol A.
大多数乳腺癌呈雌激素受体（ER）阳性，并具有管腔上皮表型。然而，这些 ER+ 肿瘤通常含有异质的 ER- 肿瘤细胞亚群。我们之前在 ER+ 和孕激素受体阳性 (PR+) 肿瘤中发现了一群细胞角蛋白 5 (CK5) 阳性细胞，它们既是 ER−PR− 又是 CD44+，这是乳腺肿瘤起始细胞 (TIC) 的标志物。这些 CK5+ 细胞具有腔内肿瘤异种移植物中 TIC 的特性，我们推测它们比其 ER+ 邻居更能抵抗化疗和抗 ER 靶向疗法。为了测试这一点，我们使用了 ER+PR+ T47D 和 MCF7 乳腺癌细胞。 CK5+细胞的增殖指数低于CK5−细胞，对5-氟尿嘧啶和多西紫杉醇的敏感性较低，并且处理后培养物中CK5+细胞变得富集。 CK5+细胞比CK5-细胞更不易发生药物诱导的细胞凋亡。与单独用 E 处理的对照相比，用 17β-雌二醇 (E) 加抗雌激素他莫昔芬或氟维司群处理的细胞中，ER 蛋白水平降低，CK5 蛋白水平升高。在接受新辅助内分泌治疗的患者的 ER+ 肿瘤中，与治疗前的肿瘤相比，治疗后 ER 基因表达减少，CK5 基因表达增加。与治疗前的肿瘤相比，治疗后的肿瘤中CK5+细胞的数量也有所增加。我们得出的结论是，相对于大多数 ER+PR+CK5− 细胞，在许多管腔肿瘤中发现的 ER−PR−CK5+ 亚群对标准内分泌和化疗具有耐药性。需要有效靶向这些细胞的化合物来改善管腔乳腺癌的治疗结果。
A majority of breast cancers are estrogen receptor (ER) positive and have a luminal epithelial phenotype. However, these ER+ tumors often contain heterogeneous subpopulations of ER− tumor cells. We previously identified a population of cytokeratin 5 (CK5) positive cells within ER+ and progesterone receptor positive (PR+) tumors that is both ER−PR− and CD44+, a marker of breast tumor-initiating cells (TICs). These CK5+ cells have properties of TICs in luminal tumor xenografts, and we speculated that they are more resistant to chemo- and anti-ER-targeted therapies than their ER+ neighbors. To test this, we used ER+PR+ T47D and MCF7 breast cancer cells. CK5+ cells had lower proliferative indices than CK5− cells, were less sensitive to 5-fluorouracil and docetaxel, and cultures became enriched for CK5+ cells after treatments. CK5+ cells were less prone to drug-induced apoptosis than CK5− cells. In cells treated with 17β-estradiol (E) plus anti-estrogens tamoxifen or fulvestrant, ER protein levels decreased, and CK5 protein levels increased, compared to controls treated with E alone. In ER+ tumors from patients treated with neoadjuvant endocrine therapies ER gene expression decreased, and CK5 gene expression increased in post compared to pre-treatment tumors. The number of CK5+ cells in tumors also increased in post- compared to pre-treatment tumors. We conclude that an ER−PR−CK5+ subpopulation found in many luminal tumors is resistant to standard endocrine and chemotherapies, relative to the majority ER+PR+CK5− cells. Compounds that effectively target these cells are needed to improve outcome in luminal breast cancers.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
50.5
作者：
Liedtke, C.;Broglio, K.;Gonzalez-Angulo, A. M.
通讯作者：
Gonzalez-Angulo, A. M.
影响因子：
45.3
作者：
Hugh, Judith;Hanson, John;Vogel, Charles
通讯作者：
Vogel, Charles
影响因子：
3.8
作者：
Harvell, Djuana M. E.;Spoelstra, Nicole S.;Richer, Jennifer K.
通讯作者：
Richer, Jennifer K.