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Centrosomes are membrane-free structures that function as microtubule organizing centers in most eukaryotes. Through this ability of organizing microtubules, they are mainly involved in interphase processes such as cell locomotion and maintenance of cell polarity. It is in mitosis that the centrosomes orchestrate, with utmost precision, the assembly of the mitotic spindle to ensure proper segregation of chromosomes. Prior to mitosis, a single centrosome duplicates to produce two mature centrosomes. Centrosome amplification due to errors in centrosome duplication is linked to aneuploidy, a hallmark of cancer. Mps1 protein kinase has an important role in centrosome duplication. Preventing the degradation of Mps1 leads to centrosome reduplication. We identified the calcium binding proteins, Centrin2 and Centrin3 (Cetn2 and Cetn3) as in-vitro substrates of Mps1. Mps1 phosphorylation sites in Cetn2 dictate the function of Cetn2 in centriole assembly and promotes centriole over-production. However, Cetn2 and Cetn3 are evolutionarily distinct and are not functionally equivalent. Here, we show that Cetn3 is a biochemical inhibitor of Mps1 kinase activity as well as a biological inhibitor of centrosome duplication. We also show that small molecule inhibitors of Mps1, Cmpd-1 and Cmpd-13 inhibit centrosome duplication and abrogate SAC activity in breast cancer cells. Cells that express non-degradable Mps1 show increased cell survival and growth in colony formation assay and prevent the formation of tumors in nude mice. Loss of function mutations in the tumor suppressor PTEN are frequently seen in many cancers, including in breast cancer, and this often leads to hyper-activation of the Akt kinase signaling pathway. We show that the phosphorylation status of Mps1 correlates with the PTEN status of breast cancer cells and that Akt phosphorylates Mps1. These data suggests an interplay between Mps1 and PTEN/Akt pathway in breast cancer cells. Thus, studying the different functions of Mps1 and its interacting partners may contribute to a better understanding of the possible link between Mps1 and breast cancer progression.