Chan S R, Rickert C G, Vermi W, Sheehan K C F, Arthur C, Allen J A, White J M, Archambault J, Lonardi S, McDevitt T M, Bhattacharya D, Lorenzi M V, Allred D C, Schreiber R D
Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
1] Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA [2] Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia School of Medicine, Piazzale Spedali Civili 1, Brescia 25123, Italy.
Cell Death Differ. 2014 Feb;21(2):234-46. doi: 10.1038/cdd.2013.116. Epub 2013 Sep 13.
We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-α-positive (ERα(+)) breast cancers and mice lacking STAT1 spontaneously develop ERα(+) mammary tumors. However, the precise mechanism by which STAT1 suppresses mammary gland tumorigenesis has not been fully elucidated. Here we show that STAT1-deficient mammary epithelial cells (MECs) display persistent prolactin receptor (PrlR) signaling, resulting in activation of JAK2, STAT3 and STAT5A/5B, expansion of CD61(+) luminal progenitor cells and development of ERα(+) mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1(-/-) MECs. Prophylactic use of a pharmacological JAK2 inhibitor restrains the proportion of luminal progenitors and prevents disease induction. Systemic inhibition of activated JAK2 induces tumor cell death and produces therapeutic regression of pre-existing endocrine-sensitive and refractory mammary tumors. Thus, STAT1 suppresses tumor formation in mammary glands by preventing the natural developmental function of a growth factor signaling pathway from becoming pro-oncogenic. In addition, targeted inhibition of JAK2 may have significant therapeutic potential in controlling ERα(+) breast cancer in humans.
我们之前报道过，在人类雌激素受体α阳性（ERα(+)）乳腺癌中，STAT1表达常常缺失，并且缺乏STAT1的小鼠会自发形成ERα(+)乳腺肿瘤。然而，STAT1抑制乳腺肿瘤发生的确切机制尚未完全阐明。在此我们表明，STAT1缺陷的乳腺上皮细胞（MECs）表现出持续的催乳素受体（PrlR）信号传导，导致JAK2、STAT3和STAT5A/5B激活，CD61(+)管腔祖细胞扩增以及ERα(+)乳腺肿瘤的发生。无法上调SOCS1（一种由STAT1诱导的JAK2抑制剂）导致STAT1(-/-) MECs中致癌性PrlR信号传导不受抑制。预防性使用一种药理学JAK2抑制剂可抑制管腔祖细胞的比例并预防疾病诱导。对活化的JAK2进行全身抑制可诱导肿瘤细胞死亡，并使已存在的内分泌敏感和难治性乳腺肿瘤产生治疗性消退。因此，STAT1通过防止生长因子信号通路的自然发育功能转变为促癌功能来抑制乳腺肿瘤形成。此外，靶向抑制JAK2在控制人类ERα(+)乳腺癌方面可能具有显著的治疗潜力。
