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 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 RXRα 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'.
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Jacqulyne P
JP
Robichaux
Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
John W
JW
Fuseler
Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
Shrusti S
SS
Patel
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Steven W
SW
Kubalak
Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
Adam
A
Hartstone-Rose
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA ann.ramsdell@uscmed.sc.edu.|Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.|Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.|Program in Women's and Gender Studies, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208, USA.
Ann F
0000-0003-2469-7079
AF
Ramsdell
D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D005260:Female; D008321:Mammary Glands, Animal / Q000196:embryology*; D051379:Mice; D038081:Organogenesis; D047490:Retinoid X Receptor alpha / Q000235:genetics* / Q000378:metabolism
D047490:Retinoid X Receptor alpha
breast cancer; ductal epithelium; left–right asymmetry; mammary gland development; retinoid X receptor alpha; symmetry