Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Nat Med. 2018 May;24(4):463-473. doi: 10.1038/nm.4494. Epub 2018 Mar 12.
Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.
基底样、激素受体阴性的乳腺癌亚型仍然是一个临床未满足的挑战，因为在治疗后，患者的复发率和生存率都很高。恶性乳腺上皮细胞及其下基质的共同进化促使癌症相关成纤维细胞（CAF）支持癌症进展的大多数特征，如果不是全部的话。在这里，我们描述了 CAF 作为乳腺癌分子亚型决定因素的以前未被认识到的作用。我们在人基底样乳腺癌中鉴定了表达血小板衍生生长因子（PDGF）-CC 的癌细胞与表达同源受体的 CAF 之间的旁分泌串扰。在癌症小鼠模型中，PDGF-CC 活性的遗传或药物干预导致基底样乳腺癌向激素受体阳性状态的转化，从而增强了先前耐药肿瘤对内分泌治疗的敏感性。我们得出结论，乳腺癌向基底样亚型的特化受微环境控制，并具有治疗可操作性。
