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 developL-Rasynchronously—thatRApathwayperturbationwould likewise result in asymmetricmammary 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 theRXRα^+/- thoracicmammary gland(TMG) pairs exhibited significant L-R asymmetry,with left-side reduction in network size. InRXRα^+/- TMGs in which symmetry wasmaintained, networks had bilaterally increased size, with left networks showing greater variability in area and pattern. Reminiscent of posterior somites, whose bilateral symmetry is refractory to RA attenuation, inguinal mammary glands (IMGs) also had bilaterally increased network size, but no loss of symmetry. Together, these results demonstrate that mammary glands exhibit differential A-P sensitivity to RXRa heterozygosity, with ductal network symmetry markedly compromised in anterior but not posterior glands. As TMGs more closely model human breast development than IMGs, these findings raise the possibility that for some women, breast cancer risk may initiate with subtle axial patterning defects that result in L-R asymmetric growth and pattern of the mammary ductal epithelium. This article is part of the themed issue ‘Provocative questions in left-right asymmetry’.