Regulation of lipid synthesis in estrogen receptor positive breast cancer

 描述（由申请人提供）：癌细胞代谢的改变被认为是一个重要的“致命弱点”，可用于开发靶向癌症治疗。特别是，由于其在产生新的细胞膜和信号分子中的作用，从头脂肪生成（DNL）越来越被认为是癌症生长的重要途径。然而，人们对癌症中DNL的调节机制知之甚少。我们认为，对i）控制DNL的因素和机制以及ii）DNL脂质产物的性质和功能的更深入了解将为靶向DNL和治疗复发/耐药ER+乳腺癌提供新的治疗策略。使用各种方法和模型，我们已经建立了SREBP 1和2，主转录调节脂肪酸和胆固醇合成，分别调节关键酶的脂质合成，以及DNL本身，在内分泌敏感和耐药雌激素受体阳性乳腺癌细胞。此外，SREBP活性对于i）对内分泌疗法敏感的ER+乳腺癌细胞的细胞依赖性增殖，ii）内分泌抗性ER+乳腺癌细胞的细胞非依赖性增殖，和iii）内分泌抗性细胞的侵袭是必需的。我们发现SREBP的表达和活性在几种ER+乳腺癌细胞系中受雌二醇（E2）和/或生长因子IGF-1的调控。此外，我们已经确定了E2和IGF-1可能调节SREBPs表达和活性的两种潜在机制。基于这些发现，我们假设激素调节SREBP的表达和活性导致肿瘤生长所必需的特异性脂质介质的从头合成 内分泌敏感型和耐药型乳腺癌。为了验证这一假设，我们建议在细胞系来源和患者来源的肿瘤异种移植物中进行研究，以1）确定ER+乳腺肿瘤中SREBP活性的功能，2）鉴定DNL的生物学重要脂质产物，3）研究生长的ER+乳腺肿瘤中DNL的激素调节。总之，这些研究的结果将促进我们对DNL在乳腺癌中的调节和功能的理解，包括对内分泌治疗敏感或耐药的ER+癌症之间的差异。通过深入了解这些差异，我们的工作将为开发新的治疗策略提供令人信服的基础，以靶向复发/耐药ER+乳腺癌中的DNL及其脂质产物。

 DESCRIPTION (provided by applicant): Alterations in cancer cell metabolism are thought to represent an important "Achille's heel" that can be exploited for developing targeted cancer therapies. In particular, de novo lipogenesis (DNL) is increasingly recognized as an essential pathway for cancer growth due to its role in generating new cell membranes and signaling molecules. However, little is known about what regulates DNL in cancers. We propose that a greater understanding of i) the factors and mechanisms controlling DNL and ii) the nature and function of lipid products of DNL will provide new therapeutic strategies to target DNL and treat recurrent/resistant ER+ breast cancers. Using a variety of approaches and models, we have established that SREBP1 and 2, the master transcriptional regulators of fatty acid and cholesterol synthesis, respectively, regulate key enzymes for lipid synthesis, as well as DNL itself, in endocrine sensitive and resistant estrogen receptor positive breast cancer cells. Moreover, SREBP activity is essential for i) hormone-dependent proliferation of ER+ breast cancer cells that are sensitive to endocrine therapy, ii) hormone-independent proliferation of endocrine-resistant ER+ breast cancer cells, and iii) invasion of endocrine-resistant cells. We find that SREBP expression and activity are hormonally regulated by estradiol (E2) and/or the growth factor IGF-1 in several ER+ breast cancer cell lines. Additionally, we have identified two potential mechanisms by which E2 and IGF-1 may regulate SREBPs expression and activity. Based on these findings, we hypothesize that hormonal regulation of SREBP expression and activity leads to de novo synthesis of specific lipid mediators that are essential for tumor growth in endocrine-sensitive and resistant breast cancers. To test this hypothesis, we propose to conduct studies in in cell line-derived and patient-derived tumor xenografts to 1) define the function of SREBP activity in ER+ breast tumors, 2) identify biologically important lipid products of DNL, and 3) investigate hormonal regulation of DNL in growing ER+ breast tumors. Together, the results of these studies will advance our understanding of the regulation and function of DNL in breast cancer, including differences between ER+ cancers that are sensitive or resistant to endocrine-therapy. By gaining a deeper understanding of these differences, our work will provide a compelling basis for developing novel therapeutic strategies to target DNL and its lipid products in recurrent/resistant ER+ breast cancers.