Bi-directional interactions with tumor microenvironment enhance BRCA1-IRIS overexpressing TNBC tumor cells aggressiveness

 描述(由申请人提供)：与肿瘤微环境的双向相互作用增强过表达TNBC肿瘤细胞的BRCA1-IRIS侵袭性。TNBC是一种侵袭性乳腺癌，缺乏ER/PR表达和Her2扩增，因此缺乏靶向治疗。TNBC在非裔美国女性中的比例过高，大多数生活在密西西比州。TNBC是一种侵袭性强、进展迅速的疾病，可转移到肺、肝和脑。BRCA1-IRIS在大多数TNBC中上调。BRCA1-IRIS过表达(以下简称IRISOE)促进TNBC肿瘤的形成和转移，其沉默可阻止两者的形成和转移。本研究的目的是确定IRISOE促进转移的分子机制(S)。我们的中心假设是，由于IRISOE引发的大量增殖，IRISOE肿瘤的核心变得无血管和坏死。在这些坏死核心(我们将这个坏死/缺氧核心称为侵袭性小生境)周围形成的缺氧加剧了IRISOE肿瘤细胞的转移能力。我们的数据表明，在生态位，低氧触发IRISOE/TNBC肿瘤细胞分泌IL-6，并诱导MSCs表达IL-6R。这个信号环将MSCs吸引到IRISOE/TNBC肿瘤细胞附近，并激活它们分泌PGE2。PGE2通过EP2/4与IRISOE/TNBC肿瘤细胞结合，重新激活IRISOE/TNBC肿瘤细胞分泌其他细胞因子，如GM-CSF和VEGF。GM-CSF是内皮细胞(EC)单核细胞和血管内皮细胞生长因子(VEGF)的有效募集者。GM-CSF与肿瘤相关巨噬细胞(TAMs)上的CSF-2R结合，VEGF与ECs上的VEGFR结合，将它们招募到IRISOE/TNBC肿瘤细胞附近，并激活它们对分泌因子，如TAMS的转化生长因子-1？和ECs的IL8。除PGE2/EP2/4外，在IRISOE/TNBC肿瘤细胞上，转化生长因子-1与TüRI/II结合，IL-8与CXCR1/2结合，可增强IRISOE/TNBC细胞的侵袭力及其转移能力。在特定的目标一，我们将验证IRISOE/TNBC肿瘤细胞与促进IRISOE/TNBC肿瘤细胞侵袭性的MSCs之间的双向相互作用。在特定的目标二，我们将验证IRISOE/TNBC肿瘤细胞与M2-TAMs之间的双向相互作用，以促进IRISOE/TNBC肿瘤细胞的侵袭性。最后，在特定的目标三，我们将验证IRISOE/TNBC肿瘤细胞之间的双向相互作用和ECs促进IRISOE/TNBC肿瘤细胞侵袭性的作用。拟议的研究符合美国国立卫生研究院的目标，即更好地了解推动乳腺癌进展的机制，并为早期发现和治疗靶点产生有效的生物标记物。我们相信，我们的资助符合所有这些标准，并为开发抗BRCA1-IRIS药物提供了令人信服的治疗理由，该药物专门针对复发风险高和预后差的患者的TNBC肿瘤细胞。

 DESCRIPTION (provided by applicant): Bi-directional interactions with tumor microenvironment enhance BRCA1-IRIS overexpressing TNBC tumor cells aggressiveness. TNBC is an aggressive breast cancer lacks ER/PR expression and Her2 amplification, therefore lacks targeted therapy. TNBC is over-represented in African American women, the majority live in Mississippi. TNBC is an aggressive rapidly advanced disease that metastasizes to lung, liver, and brain. BRCA1-IRIS is upregulated in the majority of TNBC. BRCA1-IRIS overexpression (hereafter IRISOE) promotes formation and metastasis of TNBC tumors, and its silencing prevents both. The objective of this study is to identify the molecular mechanism(s) responsible for enhanced metastasis by IRISOE. Our central hypothesis is that due to massive proliferation triggered by IRISOE, IRISOE tumors become avascular and necrotic in their cores. Hypoxia developed in areas surrounding these necrotic cores (we refer to this necrotic/hypoxic core as the aggressiveness niche) aggravates IRISOE tumor cells metastatic ability. Our data show that in the niche, hypoxia triggers IRISOE/TNBC tumor cells to secrete IL-6 and that induces IL-6R expression on MSCs. This signaling loop attracts MSCs to the vicinity of IRISOE/TNBC tumor cells and activates them to secrete PGE2. PGE2 binds to IRISOE/TNBC tumor cells through EP2/4 re-activates IRISOE/TNBC tumor cells to secrete other cytokines, e.g., GM-CSF and VEGF. GM-CSF is a potent recruiter of monocytes and VEGF of endothelial cells (EC). GM-CSF binding to CSF-2R on tumor associated macrophages (TAMs) and VEGF binding to VEGFR on ECs recruit them to the vicinity of IRISOE/TNBC tumor cells and activates them to secret factors, such as TGF-1ß from TAMs and IL8 from ECs. TGF-1ß binding to TßRI/II and IL8 to CXCR1/2 on IRISOE/TNBC tumor cells, in addition to PGE2/EP2/4 enhance IRISOE/TNBC cells aggressiveness and their dissemination and metastatic potential. In Specific Aim One, we will validate the bidirectional interactions between IRISOE/TNBC tumor cells and MSCs promoting IRISOE/TNBC tumor cells aggressiveness. In Specific Aim Two, we will validate the bidirectional interactions between IRISOE/TNBC tumor cells and M2- TAMs promoting IRISOE/TNBC tumor cells aggressiveness. Finally in Specific Aim Three, we will validate the bidirectional interactions between IRISOE/TNBC tumor cells and ECs role promoting IRISOE/TNBC tumor cells aggressiveness. The proposed studies are in line with the aims of the NIH of generating better understanding of the mechanisms that drive breast cancer progression and produce validated biomarkers for early detection and therapeutic targets. We believe our grant fulfills all these criteria and provide a compelling therapeutic rationale for th development of anti-BRCA1-IRIS drug to specifically target TNBC tumor cells in patients with high risk of recurrence and poor prognosis.