Yanai Ayako, Inoue Natsuko, Yagi Tomoko, Nishimukai Arisa, Miyagawa Yoshimasa, Murase Keiko, Imamura Michiko, Enomoto Yukie, Takatsuka Yuichi, Watanabe Takahiro, Hirota Seiichi, Sasa Mitsunori, Katagiri Toyomasa, Miyoshi Yasuo
Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Clin Breast Cancer. 2015 Jun;15(3):197-203. doi: 10.1016/j.clbc.2014.12.002. Epub 2014 Dec 24.
We determined the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in 108 cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with high and low Ki-67 expression. The expression levels of Ki-67, p53, phosphorylated MAPK (pMAPK), and protein S6 (pS6; downstream molecule of PI3K/Akt/mammalian target of rapamycin/S6 kinase pathway) were determined immunohistochemically. pS6 positivity, but not pMAPK positivity, was significantly associated with the high Ki-67 expression subset.
Evaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear.
We determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER(+), HER2(-) breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%.
A significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset.
From our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER(+)/HER2(-) breast cancer with high Ki-67 expression.
我们测定了108例雌激素受体阳性、人表皮生长因子受体2阴性且Ki-67表达高低不同的乳腺癌中磷酸肌醇3激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）信号通路的激活情况。通过免疫组织化学方法测定了Ki-67、p53、磷酸化MAPK（pMAPK）和蛋白S6（pS6；PI3K/Akt/雷帕霉素哺乳动物靶蛋白/S6激酶通路的下游分子）的表达水平。pS6阳性而非pMAPK阳性与高Ki-67表达亚组显著相关。
评估雌激素受体（ER）阳性、人表皮生长因子受体2（HER2）阴性乳腺癌的腔面A和腔面B特征被认为很重要。虽然磷酸肌醇3激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）信号通路被认为与腔面B亚型有关，但其对乳腺癌的具体作用细节仍不清楚。
我们测定了108例ER(+)、HER2(-)且Ki-67表达高低不同的乳腺癌病例中这些通路（磷酸化MAPK [pMAPK]和蛋白S6 [pS6；PI3K/Akt/雷帕霉素哺乳动物靶蛋白（mTOR）/S6激酶（S6K）的下游分子]）的激活情况。还通过免疫组织化学方法测定了ER、孕激素受体（PgR）、Ki-67、p53的表达水平。Ki-67的截断值设定为15%。
Ki-67高表达的癌病例中pS6阳性的比例显著高于Ki-67低表达的病例（53.2%对19.7%；P = 0.0003）。p53（23.4%对11.5%；P = 0.12）或pMAPK（36.2%对34.4%；P = 0.85）阳性在高表达和低表达病例之间未发现显著差异。多因素分析显示，pS6阳性（比值比5.16，95%置信区间1.95 - 13.63；P = 0.0009）、核分级2级和3级以及低PgR表达（≤20%）与高Ki-67亚组独立相关。
根据我们的研究结果，我们得出结论，pS6表达水平与高Ki-67表达的乳腺癌特征相关。因为这些关联在绝经状态不同的情况下均有观察到，所以生物学差异似乎受雌激素信号影响较小，而受S6蛋白激活的影响更大，尤其是在增殖方面。我们的研究结果还表明，靶向mTOR/S6K通路可能是治疗高Ki-67表达的ER(+)/HER2(-)乳腺癌的一种有用策略。
