Overexpression of Specific CD44 Isoforms Is Associated with Aggressive Cell Features in Acquired Endocrine Resistance.
Overexpression of Specific CD44 Isoforms Is Associated with Aggressive Cell Features in Acquired Endocrine Resistance.
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DOI：
10.3389/fonc.2016.00145
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发表时间：
2016
影响因子：
4.7
通讯作者：
Hiscox S
中科院分区：
文献类型：
--
作者：
Bellerby R;Smith C;Kyme S;Gee J;Günthert U;Green A;Rakha E;Barrett-Lee P;Hiscox S
虽然内分泌治疗是雌激素受体阳性乳腺癌的主要治疗手段，但这些药物的临床疗效受到与疾病复发和预后不良相关的获得性耐药现象的限制。我们之前的研究表明，获得性耐药伴随着细胞侵袭和迁移的增加，并且CD44家族蛋白在耐药表型中过表达。鉴于CD44与肿瘤进展的关联，我们假设其过表达可能促进内分泌抵抗性乳腺癌的侵袭行为。在这里，我们进一步研究了两种特异性CD44亚型CD44v3和CD44v6在内分泌抗性表型中的作用。我们的数据显示，在内分泌敏感的MCF-7细胞中，CD44v6而不是CD44v3的过表达会导致EGFR信号的增加，增强其内源性侵袭能力，并减弱其对内分泌治疗的反应。在内分泌抵抗细胞模型中，CD44v6的抑制与其侵袭能力的降低有关。我们的数据表明，在获得性耐药乳腺癌中，CD44v6的上调可能导致这些细胞的侵袭性表型增加，并通过EGFR通路的反激活导致内分泌反应的丧失。未来的治疗靶向CD44v6可能被证明是与egfr靶向药物一起延缓/预防乳腺癌获得性耐药的有效策略。
While endocrine therapy is the mainstay of ER+ breast cancer, the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance that is associated with disease relapse and poor prognosis. Our previous studies revealed that acquired resistance is accompanied by a gain in cellular invasion and migration and also that CD44 family proteins are overexpressed in the resistant phenotype. Given the association of CD44 with tumor progression, we hypothesized that its overexpression may act to promote the aggressive behavior of endocrine-resistant breast cancers. Here, we have investigated further the role of two specific CD44 isoforms, CD44v3 and CD44v6, in the endocrine-resistant phenotype. Our data revealed that overexpression of CD44v6, but not CD44v3, in endocrine-sensitive MCF-7 cells resulted in a gain in EGFR signaling, enhanced their endogenous invasive capacity, and attenuated their response to endocrine treatment. Suppression of CD44v6 in endocrine-resistant cell models was associated with a reduction in their invasive capacity. Our data suggest that upregulation of CD44v6 in acquired resistant breast cancer may contribute to a gain in the aggressive phenotype of these cells and loss of endocrine response through transactivation of the EGFR pathway. Future therapeutic targeting of CD44v6 may prove to be an effective strategy alongside EGFR-targeted agents in delaying/preventing acquired resistance in breast cancer.