Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
IfADo-Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, Dortmund, Germany.
Int J Cancer. 2015 Aug 1;137(3):686-97. doi: 10.1002/ijc.29404. Epub 2015 Jan 8.
Around 70% of breast cancers express the estrogen receptor α (ERα) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant anti-endocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERα and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERα and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERα+ breast cancer patients and induces cell death in ER+ breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERα+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERα+ breast cancer cells through suppression of ERα expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERα+ breast cancers independently of their p53 status.
大约 70%的乳腺癌表达雌激素受体 α（ERα），并且依赖雌激素来生长、存活和疾病进展。激素敏感性的存在通常与良好的预后相关。辅助内分泌治疗的使用显著降低了早期疾病患者的乳腺癌死亡率，并且内分泌治疗在晚期疾病的治疗中也发挥着核心作用。然而，一部分激素受体阳性乳腺癌不能从内分泌治疗中获益，并且几乎所有的激素受体阳性转移性乳腺癌最终都会对抗激素治疗产生耐药性。尽管对内分泌治疗耐药的机制有了新的认识，例如 ERα 和 Her2/neu 之间的串扰，但对内分泌治疗耐药的晚期激素受体阳性乳腺癌的管理仍然是一个重大挑战。在本研究中，我们证明蛋白酶体抑制剂硼替佐米强烈抑制 ERα 和 HER2/neu 的表达，增加细胞周期蛋白依赖性激酶抑制剂的表达，抑制与 ERα+乳腺癌患者预后不良相关的多个基因的表达，并在存在和不存在功能 p53 的情况下诱导 ER+乳腺癌细胞死亡。尽管硼替佐米增加了 p53 的水平，并增加了携带野生型 p53 的 ERα+乳腺癌细胞中促凋亡靶基因的表达，但硼替佐米通过抑制 ERα 表达和抑制 PI3K/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）和 ERK 信号通路，对 ERα+乳腺癌细胞也发挥了抗肿瘤作用，而不依赖于功能 p53。这些发现表明，硼替佐米有可能改善内分泌治疗耐药的 ERα+乳腺癌的管理，而与它们的 p53 状态无关。
