The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer
The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer
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DOI：
10.1016/j.celrep.2019.09.032
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发表时间：
2019-10-22
期刊：
影响因子：
8.8
通讯作者：
McDonnell, Donald P.
中科院分区：
文献类型：
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作者：
Cocce, Kimberly J.;Jasper, Jeff S.;McDonnell, Donald P.
尽管内分泌治疗对雌激素受体-α(ERα)阳性乳腺癌有积极的临床影响，但从头耐药和获得性耐药限制了现有药物的治疗寿命。站在耐药性几乎不可避免的立场，我们进行了一项研究，以识别和利用内分泌治疗耐药疾病中明显的靶向脆弱性。利用内分泌治疗敏感和耐药乳腺癌的细胞和小鼠模型，结合当代的发现平台，我们发现了一个靶向通路，它由转录因子FOXA1和GRHL2、共同调节的靶基因、膜受体LYPD3和LYPD3配体AGR2组成。使用针对LYPD3或AGR2的阻断抗体抑制这一途径的活性，可以抑制小鼠内分泌耐药肿瘤的生长，为近期针对这些蛋白的人源化抗体的临床开发提供了理论基础。
Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ER alpha)positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.