Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
Nat Commun. 2021 Nov 29;12(1):6967. doi: 10.1038/s41467-021-27220-9.
Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.
乳腺癌现已成为全球最常见的癌症和女性死亡的主要原因。三分之二的乳腺癌表达腔雌激素受体阳性（ERα+）表型，最初对激素治疗有反应，但会出现耐药性。对 ERα 通路生物学和治疗发现的理解的主要障碍是腔 ERα+乳腺癌模型的受限组合。由于尚未完全了解，ERα+表型在培养细胞中不稳定。我们检查了 400 例患者来源的乳腺上皮和乳腺癌外植体培养物（PDECs），这些培养物在各种三维基质支架中生长，发现 ERα 主要受基质硬度调节。基质硬度通过应激介导的 p38 激活和 H3K27me3 介导的表观遗传调控来上调 ERα 信号。发现基质硬度是 ERα 表型的一个重要线索，揭示了乳腺组织激素信号中的一种机械生物学成分，并为新的治疗干预措施的发展提供了可能。主题词：ER 阳性（ER+）、乳腺癌、体外模型、临床前模型、PDEC、硬度、p38 SAPK。
