Kallikrein-related peptidases (KLKs), a family of 15 serine protease members, have been consolidated as key factors in establishing several diseases, like breast cancer (BC). BC is one of the most prevalent cancers in women worldwide. Considering the lack of investigation of the role of KLKs in BC, we decided to evaluate whether KLK4 and KLK12 impact cell survival and angiogenesis. In a conditioned medium (CM) of BC cells (MCF7 cell line) stimulated with KLK4 and KLK12 (2 and 10 ng/ml x 24 h) we found using Slot blot that these KLKs: a) increase the release of insulin growth factor (IGF) and its associated binding proteins (IGFBP3 and 7), b) modify the macrophage response by paracrine BC cells signaling through the increase of the release of the colony-stimulating factor (M-CSF), c) promote a reciprocal secretion of both KLKs in an autocrine signal pathway, even more pronounced under hypoxia (1% O2 x 24 h), and d) in particular KLK12 stimulation (10 ng/ml) increased the secretion of angiogenic factors like vascular endothelial growth factor and platelet-derived growth factor A/B (PDGFA/B). KLK12 (10 ng/ml x 24 h) also increased vascular endothelial growth factor (VEGF) secretion by BC and endothelial cells (EA.hy926) in CM. It also increased the levels of PDGF-β/α and VEGF-2 receptors in these cells evaluated by western blotting. Using a commercial adhesion assay, we demonstrate that KLK4 and KLK12 (10 ng/ml) increase the adherence of BC cells to components of the extracellular matrix, such as type 4 collagen and fibrinogen. These results emphasize these proteases, KLK4 and KLK12, as positive modulators of cancer progression due to activation of crucial survival and angiogenic pathways added to its potential to modulate the adhesion and tumor environment that can contribute to metastasis. Therefore, KLK4 and KLK12 may be important targets for developing new therapies and diagnostic tools.