Mechanisms of estrogen action on bone marrow-derived stem stromal cells

人们普遍认为，怀孕后患乳腺癌的风险增加是由于 雌激素促进初始靶细胞群进一步增殖的能力。但由于 在此期间发生的大多数乳腺癌缺乏可感知的表达， 雌激素（ER）或孕激素受体（PR），这表明，如果激素的变化发挥了作用， 促进乳腺癌，他们可能不是通过直接结合激素受体分子这样做， 由乳腺上皮细胞表达。此外，众所周知，卵巢切除术可防止 雌激素受体阳性和阴性乳腺癌的妇女，进一步强调了重要性， 雌激素在雌激素受体阴性癌症的发展。 为了调和这一概念上的冲突，我们研究了雌激素促进 通过影响不同于乳腺上皮本身的宿主细胞类型，抑制ER阴性癌症的生长。我们 利用一种新的异种移植小鼠模型，其中产生的肿瘤缺乏核表达， 激素受体，重现上述临床情况。尽管缺乏ER表达，我们 表明在这个模型中发展的肿瘤需要循环雌激素来形成。 此外，我们证明，增加循环雌激素的水平足以促进 ER阴性癌症的形成和进展通过血管生成的系统性增加。值得注意的是， 新血管生成的系统性增强伴随着细胞募集的显著增加， 骨髓来源的细胞进入生长的肿瘤块，包括内皮细胞和基质细胞。基于 根据我们的证据，我们现在建议确定雌激素影响骨髓细胞的机制 募集、血管生成和肿瘤促进。 为此，我们的目标是确定宿主表达ER是否是基质效应所必需的 雌激素介导的，以及这些作用是否通过ER的基因组或非基因组作用发生 发信号。此外，我们还旨在确定骨髓间充质干细胞是否是 雌激素介导的血管生成和肿瘤促进。这将通过使用ERKO进行调查 小鼠模型，骨髓细胞分级，以及雌激素的体内和体外功能测定 发信号。最近，针对雌激素合成的上级和更特异的内分泌疗法， 已经开发了受体的基因组和非基因组活性，但是它们 仅用于治疗ER阳性乳腺癌，因为缺乏证据表明， 化合物对雌激素受体阴性肿瘤有效。因此，了解雌激素可以 促进骨髓细胞募集、血管生成和肿瘤生长将具有显著和高度的 对ER阴性癌症的相关科学和临床影响。

It is widely presumed that the increased risk of developing breast cancer following pregnancy is due to the ability estrogen to promote the further proliferation of an initiated target cell population. However, since the majority of breast cancers that do develop during this time lack appreciable expression of either the estrogen (ER)or progesterone receptors (PR), this suggests that if hormonal changes play a part in promoting breast cancer, they may not be doing so through direct binding to hormone receptor molecules expressed by breast epithelial cells. Moreover, it is well established that ovariectomy prevents the formation of both ER-positive as well as ER-negative breast cancers in women, further highlighting the importance of estrogens in the development of ER-negative cancers. To reconcile this conceptual conflict we investigated the hypothesis that estrogen promotes the outgrowth of ER-negative cancers by influencing host cell types distinct from the breast epithelium itself. We utilized a novel xenograft mouse model in which the tumors that arise lack the expression of nuclear hormone receptors, recapitulating the clinical situation described above. Despite lacking ER expression,we showed that the tumors that develop in this model require circulating estrogens for their formation. Moreover, we demonstrated that increasing the levels of circulating estrogens is sufficient to promote the formation and progression of ER-negative cancers via a systemic increase in angiogenesis. Remarkably, the systemic enhancement of neo-angiogenesis was accompanied by a striking increase in the recruitment of bone marrow derived cells into the growing tumor mass, including endothelial and stromal cells. Based on our evidence, we now propose to determine the mechanism by which estrogen effects bone marrow cell recruitment, angiogenesis and tumor promotion. To this end, we aim to determine whether ER expression by the host is necessary for the stromal effects mediated by estrogens, and whether these actions occur through the genomic or non-genomic actions of ER signaling. In addition, we also aim to determine if bone marrow mesenchymal stem cells are the targets of estrogen-mediated angiogenesis and tumor promotion. This will be investigated through the use of ERKO mouse models, bone marrow cell fractionation, and in vivo and in vitro functional assays to estrogen signaling. Most recently, superior and more specific endocrine therapies targeting estrogen synthesis, turnover, as well as genomic and non-genomic activities of the receptor have been developed, however they are only utilized for the treatment of ER-positive breast cancers due to the lack of evidence these compounds would work in ER-negative tumors. Thus, understanding the mechanism by which estrogen can promote bone marrow cell recruitment, angiogenesis, and tumor growth would have significant and highly relevant scientific and clinical impact for ER-negative cancers.