We also reported that the normal murine mammary NMuMG cells lack of mAChR expression, similarly to human MCF-10A cells, and here we showed that they are not VEGF-A producers. Similarly, we reported that human MCF-7 tumor cells, express mAChR, meanwhile human mammary normal cells MCF-10A do not. There is an important parallel between cancer and the systemic autoimmune diseases, both are characterized by a diverse collection of autoAbs directed against different antigens. Most of the antigens identified in human tumors are self-proteins without mutations but inappropriately expressed or AbMole Aristolochic-acid-A over-expressed. We had previously described the presence of autoAbs in the sera of mice LM3 tumor bearers. These autoAbs recognize and activate mAChR over-express in tumor cells, and promote tumor growth and angiogenesis, revealing that mAChR could be acting as autoantigens. Recently, we identified a similar population of autoAbs in the IgG fraction purified from the sera of breast cancer patients in stage I. Up to now, these autoAbs that interact with mAChR have been detected in all female patients studied with breast cancer in T1N0Mx. T1N0Mx-IgGs promote MCF-7 cell proliferation in vitro mainly through the activation of M3 receptor subtype that triggers phospholipase C/ nitric oxide synthase metabolic pathway. In addition, T1N0Mx-IgGs increased MCF-7 cell migration and invasion by up-regulating metalloproteinase-9 activity in tumor cell supernatants. The roles of MMPs in metastasis are multifold. They allow tumor cells to invade, intravasate and extravasate. They also allow tumor cell migration in the extracellular matrix of distant site, as well as growth and angiogenesis of secondary tumors. Regarding angiogenesis, here we demonstrate that the same autoAbs that increased MMP-9 activity in MCF-7 cell supernatants can trigger VEGF-A expression and tumor-induced angiogenesis. On line with these results, Hawinkels et al. reported that MMP-9 mRNA in gastric cancer tissues was upregulated and coincided with VEGF expression and microvascular density. These findings support an emerging notion that MMP-9 is a positive regulator of tumor angiogenesis. Moreover, the latter authors showed that neutrophil-derived MMP-9 was able to release the biologically active VEGF165 from the extracellular matrix of colon cancer. It is important to note that the stimulation of MCF-7 cellsinduced neovascular response triggered by T1N0Mx-IgG was not totally reduced in the presence of atropine, indicating that these autoAbs could be exerting pro-angiogenic actions independently of mAChR activation, and thus deepening the effects that favor tumor growth. Our results demonstrate that T1N0Mx-IgG were also able to up-regulate VEGF-A expression and angiogenesis induced by LMM3 cells in a more potent manner than in MCF-7 cells via muscarinic activation. This could be due the differences in the subtypes and amounts of mAChR express in both types of tumor cells as we reported previously: LMM3 cells express high amounts of the five subtypes of mAChR while MCF-7 cells only express M3 and M4 receptor subtypes. In conclusion our results indicate that T1N0Mx-IgG from breast cancer patients in stage I potentiate VEGF-A production and neovascular response induced by MCF-7 tumor cells by activating mAChR express in them. These autoAbs could be considered as risk factors in breast cancer progression. Development of resistance to chemotherapy in epithelial ovarian cancers involves multiple mechanisms.