Left–right analysis of mammary gland development in retinoid X receptor-α+/− mice

Left–right (L–R) differences in mammographic parenchymal patterns are an early predictor of breast cancer risk; however, the basis for this asymmetry is unknown. Here, we use retinoid X receptor alpha heterozygous null (RXRα+/−) mice to propose a developmental origin: perturbation of coordinated anterior–posterior (A–P) and L–R axial body patterning. We hypothesized that by analogy to somitogenesis—in which retinoic acid (RA) attenuation causes anterior somite pairs to develop L–R asynchronously—that RA pathway perturbation would likewise result in asymmetric mammary development. To test this, mammary glands of RXRα+/− mice were quantitatively assessed to compare left- versus right-side ductal epithelial networks. Unlike wild-type controls, half of the RXRα+/− thoracic mammary gland (TMG) pairs exhibited significant L–R asymmetry, with left-side reduction in network size. In RXRα+/− TMGs in which symmetry was maintained, networks had bilaterally increased size, with left networks showing greater variabili...