Thaler Sonja, Schmidt Marcus, Roβwag Sven, Thiede Gitta, Schad Arno, Sleeman Jonathan P
Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Obstetrics and Gynecology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Oncotarget. 2017 Aug 14;8(42):72281-72301. doi: 10.18632/oncotarget.20261. eCollection 2017 Sep 22.
Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13-15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. We further observed that proteasome inhibitors (PIs) reverse autophosphorylation and thereby inhibit the activity of constitutively active mutant HER2. We also demonstrate that PIs cause cell death in lapatinib and endocrine-resistant HER2+/ER+ breast cancer cells. These findings suggest that PIs might have the potential to improve the management of HER2+/ER+ breast cancer patients by efficiently disrupting the bi-directional HER2/ERα cross-talk.
人表皮生长因子2（HER2）癌基因的扩增和/或过表达发生在约13%-15%的浸润性乳腺癌中，并触发乳腺癌细胞的增殖、存活和转移进展。所有HER2过表达的乳腺癌中约有一半同时共表达激素受体（HR），如雌激素和孕激素受体。通过HER2及HER家族其他成员的异常信号传导介导雌激素受体α（ERα）阳性乳腺癌的内分泌抵抗。另一方面，已表明ERα共表达会减弱抗HER2治疗的效果。这些发现表明，HER2和ERα协同作用以逃避抗ERα和抗HER2靶向治疗。已经开展了合理设计的临床试验，将内分泌治疗与抗HER2药物联合使用以干扰HER2/ERα相互作用。然而，这些试验的结果表明，需要新的治疗方法来进一步提高对HER2及其他HER家族成员的抑制作用，并同时更有效地阻断ERα。在此，我们证明卡非佐米和硼替佐米可稳定HER2特异性蛋白酪氨酸磷酸酶BDP1，导致HER2自身磷酸化减少、HER2活性降低，随后PI3K/Akt通路的激活减弱，同时阻断ERα表达。我们进一步观察到蛋白酶体抑制剂（PIs）可逆转自身磷酸化，从而抑制组成型活性突变体HER2的活性。我们还证明PIs可导致拉帕替尼耐药及内分泌耐药的HER2+/ER+乳腺癌细胞死亡。这些发现表明，PIs可能有潜力通过有效破坏双向HER2/ERα相互作用来改善HER2+/ER+乳腺癌患者的治疗。
