Aneuploidy is commonly observed in breast cancer and is associated with poor prognosis. One frequent type of aneuploidy, hypertetraploidy, may derive from ploidy duplication of hyperdiploid cells. However, the pathological consequences of ploidy duplication in breast cancer progression have not been characterized. Here, we present an experimental system demonstrating spontaneous appearance of hypertetraploid cells from organ-specific metastatic variants of the MDA-MB-231 breast cancer cell line through ploidy duplication in vitro and in vivo. The hypertetraploid progenies showed increased metastatic potential to lung and brain, but not to bone, which may be partially explained by the distinct capillary structures in these organs that confer differential lodging advantages to tumor cells with enlarged size. Our results suggest a potential mechanistic link between ploidy duplication and enhancement of metastatic potentials, as was observed in previous clinical studies of breast cancer.