Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer.
Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer.
复制标题
DOI：
10.1016/j.clbc.2015.06.001
复制
发表时间：
2015-12
影响因子：
3.1
通讯作者：
Cui X
中科院分区：
文献类型：
--
作者：
Chung A;Choi M;Han BC;Bose S;Zhang X;Medina-Kauwe L;Sims J;Murali R;Taguiam M;Varda M;Schiff R;Giuliano A;Cui X
我们在接受曲妥珠单抗治疗的Her 2+乳腺癌患者和Her 2+乳腺癌细胞系中研究了基础蛋白表达对曲妥珠单抗应答的影响。在接受化疗/曲妥珠单抗治疗的97例1-3期Her 2+乳腺癌患者的石蜡包埋组织中进行免疫组织化学染色后，评价了CK 5/6、CK 14和EGFR的表达。比较有和无基础蛋白表达的组的临床病理参数和生存率。我们用载体、曲妥珠单抗（T）、紫杉醇（P）和T+ P处理4种细胞系（2种基础-Her 2（HCC 1569、HCC 1954）和2种非基础-Her 2（BT 474、SKBR 3））。使用免疫印迹评估细胞活力并比较组间Her 2途径抑制。乳腺球形成用于评估BCSC性质。EFGR表达与癌症特异性生存率（CSS）显著相关（p=0.05）。CK 5/6表达与总体（OS）、无病生存期（DFS）和CSS密切相关（分别为p=0.03、p=0.04和p=0.03）。调整协变量后，EGFR和CK 5/6保持统计学显著性。CK 14与生存率无关。所有细胞系表达相似水平的Her 2。T和P单独抑制非基底细胞系的增殖; T+P具有相加的细胞毒性作用。基底细胞对T有抗性，P抑制增殖，但T+P对基底细胞生长无相加性细胞毒作用。免疫印迹显示，在用T或T+P处理后，非基底细胞中的p-Akt水平显著降低，但在基底细胞中没有。Akt阻断抑制基底和非基底Her 2+细胞的生长。此外，基底Her 2细胞系具有增加的乳腺球形成，表明与非基底Her 2细胞系相比增加的干细胞性质。CK 5/6和EGFR表达预测接受曲妥珠单抗治疗的Her 2+乳腺癌患者的预后较差。Basal-Her 2乳腺癌细胞系对通过Akt途径介导的曲妥珠单抗具有耐药性; AKT抑制可消除这种耐药性。基础Her 2细胞系也具有增加的干细胞特性，这可能在抗性途径中起作用
We investigated the effect of basal protein expression on trastuzamab response in patients with Her2+ breast cancer who received trastuzamab and in Her2+ breast cancer cell lines. Expression of CK5/6, CK14, and EGFR was evaluated after immunohistochemical staining in paraffin-embedded tissue of 97 patients with Stage 1-3 Her2+ breast cancer treated with chemotherapy/trastuzamab. Groups with and without basal protein expression were compared with respect to clinicopathologic parameters and survival. We treated 4 cell lines (2 basal-Her2(HCC1569, HCC1954) and 2 non-basal-Her2(BT474, SKBR3)) each with vehicle, trastuzamab (T), Paclitaxel (P), and T+P. Cell viability was assessed and Her2 pathway suppression was compared between groups using immunoblotting. Mammosphere formation was used to assess BCSC properties. EFGR expression was significant associated with cancer-specific survival (CSS) (p=0.05). CK5/6 expression strongly correlated with overall (OS), disease-free survival (DFS), and CSS (p=0.03, p=0.04, and p=0.03, respectively). Statistical significance was maintained for EGFR and CK5/6 after adjusting for covariates. CK14 was not associated with survival. All cell lines expressed similar levels of Her2. Both T and P alone inhibited proliferation of non-basal cell lines; T+P had an additive cytotoxic effect. Basal cells were resistant to T, P inhibited proliferation, but T+P had no additive cytotoxic effect on cell growth in basal cells. Immunoblotting showed a significant decrease in p-Akt levels after treatment with T or T+P in non-basal cells but not in basal cells. Akt blockade suppressed growth of basal and non-basal Her2+ cells. Furthermore, basal Her2 cell lines had increased mammosphere formation suggesting increased stem cell properties compared to non-basal Her2 cell lines. CK5/6 and EGFR expression are predictive of worse prognosis in Her2+ breast cancer patients treated with trastuzamab. Basal-Her2 breast cancer cell lines are resistant to trastuzamab which is mediated through the Akt pathway; AKT inhibition abrogates this resistance. Basal Her2 cell lines also have increased stem cell properties which may play a role in the resistance pathway