IGF-II regulation of FABPs in the breast cancer survival disparity among AA women

描述(由申请人提供)：有充分的文件证明，非裔美国人(AA)患者的乳腺癌(BC)状态更晚期，存活率低于白人美国人(CA)。造成这种差异的部分原因是社会经济因素；然而，社会和环境因素的相互作用也可以调节生物因素。一个经典的例子是哺乳在预防女性乳腺癌方面具有保护作用。一些研究表明，社会因素、种族、民族差异和社会经济地位如何影响母亲母乳喂养的开始、频率和持续时间。这些因素也会影响母亲是否母乳喂养以及母乳喂养多久的决定。流行病学数据表明，人类早年怀孕和哺乳可降低患乳腺癌的风险。然而，这种对人类的保护作用的机制尚不清楚。对小鼠和大鼠的研究表明，哺乳可以刺激细胞内脂肪酸结合蛋白(FABP)的表达。不同的FABPs(1-9)在特定的组织中表达，如心脏、脑、肝脏等。FABP3在哺乳期大鼠乳腺组织中的表达显著增加，其表达调节哺乳期启动的保护作用。FABP3也在人的乳腺组织中检测到，它被称为乳房衍生生长抑制物(MDGI)，因为它对细胞增殖有很强的抑制作用。另一个确凿的事实是，FABP具有补偿关系，即当y-FABP降低时，x-FABP水平增加。因此，由于FABP3抑制乳腺细胞的增殖，我们推测该蛋白在乳腺组织中的差异表达将与乳腺癌的进展相关。因此，我们假设AA女性的FABP3水平较低，因为AA女性的哺乳率在CA、西班牙裔(HA)和亚裔美国女性中是最低的。类似地，我们推断，再生障碍性贫血妇女的组织中FABP5水平(也在乳房中检测到)会更高，以弥补FABP3水平的下降。因此，我们建议评估这些FABP在AA和CA配对的正常/肿瘤BC组织中的表达(从人类合作组织网络获得)，以确定AA妇女中FABP3的低表达/FABP5的高表达是否与AA和CA BC患者之间观察到的BC进展的差异有关。为了表征与FABP3和FABP5调控相关的潜在机制，我们还将使用从ATCC获得的CA和AA患者建立的细胞系。FABP的蛋白水平将通过蛋白质印迹、ELISA法和共聚焦免疫荧光法进行评估。MRNA水平将通过定量RT-PCR进行评估。由于哺乳是由催乳素和IGF-II调节的，我们还将确定这些蛋白质如何调节AA和CA妇女建立的BC细胞系的FABP和细胞分化。如果成功，我们的研究将提供有关哺乳在乳房中诱导的保护作用机制的迫切需要的信息，并可能为乳腺癌的预防性治疗提供新的工具。 公共卫生相关性：就癌症相关死亡而言，乳腺癌仅次于肺癌，因此，降低乳腺癌的发病率是一项重要的卫生目标。与高加索女性相比，非洲裔美国女性的乳腺癌死亡率高得不成比例。除了社会经济方面的担忧外，FABP表达的差异等生物学因素也可能导致这种生存差异。我们的研究将提供有关哺乳在乳房中诱导的保护作用的机制方面的急需的信息，并可能为乳腺癌的预防性治疗提供新的工具。

DESCRIPTION (provided by applicant): It is well documented that African-American (AA) patients present with more advanced states of breast cancer (BC) and have lower survival rates than Caucasian-Americans (CA). Some of this disparity is due to socioeconomic factors; however interaction of social and environmental factors can also modulate biological factors. A classic example is the protective effect that lactation has in preventing breast cancer in women. Several studies have shown how social factors, race, ethnic differences and socioeconomic status affect initiation, frequency, and duration of breastfeeding practices of mothers. These factors also affect a mother's decision whether or not to breastfeed and for how long she will breastfeed. Epidemiological data have shown that pregnancy and lactation at early age in humans reduces the risk of breast cancer. Nevertheless, the mechanism of this protective effect in humans is unknown. Studies in mice and rats have shown that lactation stimulates the expression of intracellular fatty-acid binding proteins (FABPs). Different FABPs (1-9) are expressed in specific tissues such as heart, brain, liver, etc. FABP3 expression is significantly increased in breast tissue of lactating rats and its expression regulates the protective effect initiated by lactation. FABP3 is also detected in human breast tissue and it is known as mammary-derived growth inhibitor (MDGI) because it has a strong inhibitory effect on cell proliferation. Well established is also the fact that FABPs have a compensatory relationship, i.e., levels of x-FABP increase when y-FABP is decreased. Therefore, since FABP3 inhibits breast cell proliferation, we reasoned that differential expression of this protein in breast tissues will correlate with breast cancer progression. Thus, we hypothesize that AA women will have lower levels of FABP3 since lactation rates among AA women are the lowest among CA, Hispanic (HA) and Asian American women. Similarly, we reasoned that FABP5 levels (also detected in breast) will be higher in tissues from AA women to compensate for the decrease in FABP3. Therefore we propose to assess the expression of these FABPs in paired normal/tumor BC tissues from AA and CA (obtained from Human Cooperative Tissue Network) to determine if lower expression of FABP3/higher expression of FABP5 among AA women is associated with the disparity in BC progression observed between AA and CA BC patients. To characterize the potential mechanisms associated with the regulation of FABP3 and FABP5 we will also use cell lines established from CA and AA patients obtained from ATCC. Protein levels of FABPs will be assessed by Western blotting, Elisa Assays and confocal immunofluorescence. mRNA levels will be assessed by quantitative rt-PCR. Since lactation is regulated by prolactin and IGF-II, we will also determine how these proteins regulate FABPs and cellular differentiation of the BC cell lines established from AA and CA women. If successful, our studies will provide much needed information about the mechanisms involved in the protective effect lactation induces in the breast and will potentially offer new tools for preventive breast cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is second only to lung cancer in terms of cancer-related death, and therefore, reducing the incidence of breast cancer is a critical health objective. African-American women have been shown to suffer from disproportionately high levels of breast cancer death compared to Caucasian women. In addition to socioeconomic concerns, biological factors such as differences in the expression of FABPs may contribute to this survival disparity. Our studies will provide much needed information about the mechanisms involved in the protective effect lactation induces in the breast and will potentially offer new tools for preventive breast cancer treatment.