PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis
PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis
复制标题
DOI：
10.1038/cdd.2014.62
复制
发表时间：
2014-09-01
影响因子：
12.4
通讯作者：
Paul, S.
中科院分区：
文献类型：
--
作者：
Paul, A.;Gunewardena, S.;Paul, S.
三阴性乳腺癌（Triple-negative breast cancer，TNBC）是一种缺乏雌激素受体（estrogen receptor，ER）、孕激素受体（progesterone receptor，PR）和表皮生长因子受体2（epidermal growth factor receptor 2，HER 2/neu）的乳腺癌，具有较高的复发率和转移率。由于缺乏ER、PR和HER 2/neu表达，TNBC患者对可用于乳腺癌治疗的HER 2导向和内分泌疗法不敏感。在这里，我们报告了非典型蛋白激酶C亚型，PKC λ/iota的表达，在所有浸润性乳腺癌（浸润性导管癌或IDC）亚型，包括TNBC亚型，显着增加和激活。由于缺乏针对TNBC的靶向治疗，我们选择研究PKC λ/iota信号传导作为TNBC的潜在治疗靶点。我们的观察表明，PKC λ/iota信号传导在乳腺癌侵袭性进展期间高度活跃，并且转移性乳腺癌（在TNBC患者中更频繁地发展的乳腺癌疾病的晚期）也以高水平的PKC λ/iota表达和活化为特征。在实验小鼠模型中的功能分析揭示，PKC λ/i ota的消耗显著降低TNBC生长以及肺转移定植。此外，我们已经确定了一个PKC λ/i调节的基因签名，由110个基因组成，这是显着相关的惰性到浸润性进展的人乳腺癌和预后不良。从机制上讲，细胞因子如TGF β和IL 1 β可以激活TNBC细胞中的PKC λ/1信号传导，并且PKC λ/1的消耗损害NF-κ B p65（RelA）核定位。我们观察到，酪氨酸-PKC λ/iota-RelA信号轴，至少部分地，参与调节基因表达，以调节TNBC细胞的侵袭。总体而言，我们的结果表明，诱导和激活PKC λ/iota促进TNBC生长，侵袭和转移。因此，靶向PKC λ/1信号传导可能是乳腺癌（包括TNBC亚型）的治疗选择。
Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKC lambda/iota, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKC lambda/iota signaling as a potential therapeutic target for TNBC. Our observations indicated that PKC lambda/iota signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKC lambda/iota expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKC lambda/iota significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKC lambda/iota-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGF beta and IL1 beta could activate PKC lambda/iota signaling in TNBC cells and depletion of PKC lambda/iota impairs NF-kappa B p65 (RelA) nuclear localization. We observed that cytokine-PKC lambda/iota-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKC lambda/iota promote TNBC growth, invasion and metastasis. Thus, targeting PKC lambda/iota signaling could be a therapeutic option for breast cancer, including the TNBC subtype.