Ishida Naoko, Baba Motoi, Hatanaka Yutaka, Hagio Kanako, Okada Hiromi, Hatanaka Kanako C, Togashi Kenichi, Matsuno Yoshihiro, Yamashita Hiroko
Department of Breast Surgery, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan.
Department of Surgical Pathology, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan.
Oncotarget. 2018 Apr 3;9(25):17711-17724. doi: 10.18632/oncotarget.24845.
Although endocrine therapy is the most important treatment option in estrogen receptor (ER)-positive breast cancer, new strategies, such as molecular targeted agents together with endocrine therapy are required to improve survival. is the most frequent mutated gene in ER-positive early breast cancers, and mutation status is reported to affect activation of AKT and ERα. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR). In this study, we examined expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERα Ser167 (ERα phospho-Ser167) by immunohistochemistry in ER-positive, HER2-negative early breast cancer. gene mutations were also detected in genomic DNA extracted from tumor blocks. Correlations between these biological markers, clinicopathological factors and prognosis were analyzed. Levels of AKT phospho-Ser473 were significantly higher in premenopausal women than in postmenopausal women. In contrast, AR expression was significantly higher in postmenopausal women than in premenopausal women. mutations were detected in 47% in premenopausal women and 47% in postmenopausal women. Postmenopausal women with wild-type tumors had significantly worse disease-free survival than patients with mutant tumors. Low levels of AKT phospho-Ser473 and high levels of ERα phospho-Ser167 were strongly associated with increased disease-free survival in postmenopausal women. Evaluation of ERα activation, in addition to mutation status, might be helpful in identifying patients who are likely to benefit from endocrine therapy alone versus those who are not in postmenopausal ER-positive early breast cancer.
尽管内分泌治疗是雌激素受体（ER）阳性乳腺癌最重要的治疗选择，但仍需要新的策略，如分子靶向药物与内分泌治疗联合使用，以提高生存率。是ER阳性早期乳腺癌中最常见的突变基因，据报道其突变状态会影响AKT和ERα的激活。此外，最近的研究表明，肿瘤表达ER、雄激素受体（AR）和维生素D受体（VDR）的患者预后较好。在本研究中，我们通过免疫组织化学检测了ER阳性、HER2阴性早期乳腺癌中AR和VDR的表达、AKT丝氨酸（Ser）473的磷酸化（AKT磷酸化-Ser473）和ERα Ser167的磷酸化（ERα磷酸化-Ser167）。还在从肿瘤组织块中提取的基因组DNA中检测了基因突变。分析了这些生物标志物、临床病理因素与预后之间的相关性。绝经前女性的AKT磷酸化-Ser473水平显著高于绝经后女性。相反，绝经后女性的AR表达显著高于绝经前女性。绝经前女性中有47%检测到突变，绝经后女性中有47%检测到突变。野生型肿瘤的绝经后女性无病生存率显著低于突变型肿瘤的患者。绝经后女性中低水平的AKT磷酸化-Ser473和高水平的ERα磷酸化-Ser167与无病生存率增加密切相关。除了突变状态外，评估ERα激活可能有助于识别绝经后ER阳性早期乳腺癌中可能仅从内分泌治疗中获益的患者与不能获益的患者。
