Jeruss Jacqueline S, Sturgis Charles D, Rademaker Alfred W, Woodruff Teresa K
Department of Neurobiology and Physiology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois 60208, USA.
Cancer Res. 2003 Jul 1;63(13):3783-90.
Activin and transforming growth factor (TGF)-beta, members of the TGF-beta superfamily of growth factors, have been implicated in both mammary gland development and breast carcinogenesis. TGF-beta is thought to be involved in the maintenance of mammary gland ductal architecture and postlactational involution. TGF-beta acts as both a tumor suppressor and has oncogenic capacities in breast cancer tissue. Activin is associated with growth modulation in glandular organs, and its receptors and signaling proteins are present and regulated during postnatal mammary gland development, primarily during the lactational phase. The presence of the major components of the activin signal transduction pathway in different pathologic grades of breast cancer tissue has not been described thoroughly, despite evidence from in vitro studies suggesting that activin can inhibit proliferation in breast cancer-derived cells. On the basis of the growth regulatory capacity of activin, we hypothesized that the components of this signal transduction system would be deregulated as breast cancer becomes more aggressive. To test this hypothesis, breast cancer samples were substratified by pathologic grade, a known prognostic marker for breast cancer, and then examined for the presence and cellular localization of activin ligand subunits (beta A- and beta B-), receptors (Act RIIA, Act RIIB, and Act RIB), and signaling proteins, Smads 2, 3, and 4, by immunohistochemistry and immunofluorescent analysis. Breast tissue from healthy patients undergoing reduction mammoplasty was also studied. The activin beta A-subunit was present in all of the tissues examined, whereas the beta B-subunit, activin type II receptors, and Smads were less evident in high-grade cancers. Significant correlations were made in breast cancer specimens between a decrease in nuclear Smad 3 abundance and high tumor grade, high architectural grade, larger tumor size, and hormone receptor negativity. Thus, activin signal transduction components are present in normal tissue and grade 1 cancer but down-regulated in high-grade cancer. The deregulation of this signal transduction system may be relevant to advancing oncogenic progression.
激活素和转化生长因子（TGF）-β是TGF-β生长因子超家族的成员，与乳腺发育和乳腺癌发生均有关联。TGF-β被认为参与乳腺导管结构的维持以及产后乳腺退化。TGF-β在乳腺癌组织中既发挥肿瘤抑制作用，也具有致癌能力。激活素与腺器官的生长调节相关，其受体和信号蛋白在出生后乳腺发育过程中存在并受到调控，主要是在泌乳期。尽管体外研究证据表明激活素可抑制乳腺癌衍生细胞的增殖，但不同病理分级的乳腺癌组织中激活素信号转导途径主要成分的存在情况尚未得到充分描述。基于激活素的生长调节能力，我们推测随着乳腺癌变得更具侵袭性，该信号转导系统的成分会失调。为验证这一假设，将乳腺癌样本按病理分级（一种已知的乳腺癌预后标志物）进行亚分层，然后通过免疫组织化学和免疫荧光分析检测激活素配体亚基（βA-和βB-）、受体（激活素受体IIA、激活素受体IIB和激活素受体IB）以及信号蛋白Smad 2、3和4的存在情况及细胞定位。还研究了接受缩乳手术的健康患者的乳腺组织。激活素βA亚基存在于所有检测的组织中，而βB亚基、激活素II型受体和Smad在高级别癌症中不太明显。在乳腺癌标本中，核Smad 3丰度降低与高肿瘤分级、高组织学分级、更大肿瘤尺寸和激素受体阴性之间存在显著相关性。因此，激活素信号转导成分存在于正常组织和1级癌症中，但在高级别癌症中下调。该信号转导系统的失调可能与肿瘤发生进展相关。
