Background: In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.Purpose: Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways. Results: 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation. Conclusions: Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages.
背景：在肿瘤中，体细胞突变可能通过改变调控通路驱动DNA损伤反应，从而加剧基因组不稳定性与增殖活性。这一认知催生了当前标准的癌症治疗策略：破坏肿瘤中突变激活的DNA修复通路。 目的：论证癌细胞并非必须消灭的敌人，而是保留着生理调控通路残余功能的病变人类细胞。 结果：1. 基因组不稳定性与癌症发展可能源于雌激素信号传导缺陷而非过度激活；2.具有基因组不稳定性的健康细胞通过体细胞突变协助DNA修复；3.肿瘤细胞的体细胞突变旨在修复DNA损伤而非加剧基因组紊乱；4.在肿瘤微环境中，雌激素信号传导驱动DNA稳定化通路，最终导向凋亡性死亡；5.在肿瘤周围细胞浸润区，肿瘤的基因组损伤会诱导炎性细胞因子分泌并促进雌激素合成，炎性细胞中生长因子受体信号通路的增强可导致雌激素受体非配体激活；6.在对基因毒性治疗敏感的乳腺癌细胞中，结构性突变有助于上调雌激素信号传导并引发后续凋亡；而在治疗不敏感的乳腺肿瘤中，通过配体或非配体途径激活雌激素受体的可能性均已耗尽，导致更严重的基因组不稳定性和不受控增殖。 结论：在分子层面理解人类肿瘤的本质特征与行为模式表明，我们应当学习肿瘤的基因组修复机制，通过支持性疗法加以引导，而非制造额外的基因组损伤。
肿瘤(癌症)患者之家