Paulson K Eric, Rieger-Christ Kimberly, McDevitt Michael A, Kuperwasser Charlotte, Kim Jiyoung, Unanue Vincent E, Zhang Xiaowei, Hu Maowen, Ruthazer Robin, Berasi Stephen P, Huang Chun-Yin, Giri Dilip, Kaufman Seth, Dugan John M, Blum Joanne, Netto Georges, Wazer David E, Summerhayes Ian C, Yee Amy S
Department of Biochemistry and Program in Genetics, Tufts University School of Medicine, Boston, MA 02111, USA.
Cancer Res. 2007 Jul 1;67(13):6136-45. doi: 10.1158/0008-5472.CAN-07-0567.
Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis.
浸润性乳腺癌有很高的复发至不可治愈疾病的风险，需要改进的预后和治疗工具。我们的工作结合临床和分子分析表明，转录抑制因子HBP1可能是浸润性乳腺癌的一个新靶点。先前的研究表明，HBP1调节细胞增殖和衰老，并抑制Wnt信号通路。其中两项功能与浸润性乳腺癌有关。在76例乳腺肿瘤中，我们鉴定出10个与完全浸润性乳腺癌相关的HBP1突变/变体。在另一项分析中，我们发现一部分浸润性乳腺癌标本的HBP1 mRNA水平也降低。这些临床相关性表明，HBP1的突变或减少发生在浸润性乳腺癌中，并且HBP1可能调节这种乳腺癌类型的增殖和侵袭性。对HBP1突变体的分析表明，它们在抑制Wnt信号通路方面存在功能缺陷。为了测试HBP1水平降低的后果，我们使用RNA干扰敲低HBP1，并在细胞和动物乳腺癌模型中观察到Wnt信号通路增加、致瘤性增殖和侵袭性增强。最后，对一个乳腺癌患者数据库的统计分析将HBP1表达降低与乳腺癌复发联系起来。在考虑复发潜力的双基因标准时，HBP1和SFRP1（另一种最近与浸润性乳腺癌相关的Wnt抑制剂）的表达降低与复发显著相关。总之，这些数据表明，HBP1可能是乳腺癌转变的一个分子和临床相关调节因子，最终导致预后不良。
