Inflammatory Breast Cancer: Factors Contributing to Dissemination

IBC是最致命的原发性乳腺癌，主要针对年轻女性。 IBC占美国所有乳腺癌病例的5%，但其发病率却很高 非裔美国女性的比例更高(10.1%)。在埃及，IBC的发病率据报道从5- 占所有乳腺癌病例的10%，而且还在上升。广泛真皮淋巴管侵犯与肿瘤栓子 这会导致淋巴管阻塞，这是该病炎症性质的基础。我们有 显示巨噬细胞渗入IBC微环境，包围IBC栓子，并存在于 IBC患者的腋血。我们在这项提议中的工作假设是IBC相关 巨噬细胞在肿瘤栓子的形成和癌细胞的扩散中起关键作用 淋巴管，IBC的两个表型特征。这项FIRCA提案的具体目标是 为了：1)建立IBC细胞的3D培养，a)评估侵袭性表型；b)确定 可能的IBC标记蛋白的表达/定位；c)量化细胞因子、趋化因子的表达 和生长因子；以及d)半胱氨酸组织蛋白的表达/分泌/活性； 表征肿瘤栓子、肿瘤、阳性淋巴中单核/巨噬细胞的表型和含量 IBC和非IBC患者的结节、腋窝支循环血和外周血；3)分离 从IBC腋下分支血和外周血单核细胞和a)定量分泌的表达 细胞因子、趋化因子和生长因子，以及b)半胱氨酸组织蛋白的表达/分泌/活性； 4)免疫组织化学石蜡切片检测选定细胞因子的细胞表面受体， 趋化因子和生长因子；以及，5)建立分离的IBC细胞和单核细胞的3D共培养 IBC腋窝分支血和外周血以及a)评估侵袭性表型；b)确定 可能的IBC标记蛋白的表达/定位；c)量化细胞因子、趋化因子的表达 和生长因子；以及d)半胱氨酸组织蛋白的表达/分泌/活性； 免疫染色共培养IBC标本中鉴定的细胞表面受体。未来方向 将使用在AIMS 1-5中获得的信息来选择半胱氨酸组织蛋白、细胞因子、趋化因子和 可能靶向降低IBC侵袭性表型的生长因子。咄咄逼人的 IBC在埃及的表现意味着迫切需要开发能够 对乳癌患者有即时的帮助。我们预计，我们的结果将 有助于描述IBC的病理生物学基础，这是 优先考虑治疗干预的新靶点。 这项研究将主要在埃及开罗大学与Mona Mostafa合作完成 Mohamed，作为美国国立卫生研究院第号补助金的延伸。R01CA131990，8-01-2008至5-31-2013。

IBC is the most lethal form of primary breast cancer and disproportionately targets younger women. IBC accounts for <5% of all breast cancer cases in the United States, but its incidence is significantly higher among African-American women (10.1%). In Egypt, the incidence of IBC is reported to be from 5- 10% of all breast cancer cases and is on the rise. Extensive dermal lymphatic invasion and tumor emboli therein result in lymphatic obstruction that underlies the inflammatory nature of the disease. We have shown that macrophages infiltrate the IBC microenvironment, surround IBC emboli and are present in axillary blood of IBC patients. Our working hypothesis in this proposal is that IBC-associated macrophages play a crucial role in the formation of tumor emboli and dissemination of the cancer cells in the lymphatics, two of the phenotypic hallmarks of IBC. The Specific Aims of this FIRCA proposal are to: 1) Establish 3D cultures of IBC cells and a) assess invasive phenotype; b) determine expression/localization of putative IBC marker proteins; c) quantify expression of cytokines, chemokines and growth factors in conditioned media; and d) expression/secretion/activity of cysteine cathepsins; 2) Characterize monocyte/macrophage phenotype and content in tumor emboli, tumors, positive lymph nodes, axillary tributary blood and peripheral blood from IBC and non-IBC patients; 3) Isolate monocytes from IBC axillary tributary blood and peripheral blood and a) quantify expression of secreted cytokines, chemokines and growth factors, and b) expression/secretion/activity of cysteine cathepsins; 4) Immunostain paraffin blocks of IBC specimens for cell surface receptors of selected cytokines, chemokines and growth factors; and, 5) Establish 3D cocultures of IBC cells and monocytes isolated from IBC axillary tributary blood and peripheral blood and a) assess invasive phenotype; b) determine expression/localization of putative IBC marker proteins; c) quantify expression of cytokines, chemokines and growth factors in conditioned media; and d) expression/secretion/activity of cysteine cathepsins; and, e) immunostain cocultures for cell surface receptors identified in IBC specimens. Future directions will use the information obtained in Aims 1-5 to select cysteine cathepsins, cytokines, chemokines and growth factors that might be targeted to reduce the invasive phenotype of IBC. The aggressive manifestation of IBC in Egypt means that there is a pressing need to develop research programs that can be of immediate assistance to patients suffering from breast cancer. We anticipate that our results will contribute to the characterization of the pathobiological underpinnings of IBC, a prerequisite for prioritizing novel targets for therapeutic intervention. This research will be done primarily in Egypt at Cairo University in collaboration with Mona Mostafa Mohamed, as an extension of NIH Grant No. R01CA131990, 8-01-2008 to 5-31-2013.