Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands

Ana Sofia Rocha (), Alejandro Collado-Solé, Osvaldo Graña-Castro, Jaime Redondo-Pedraza, Gonzalo Soria-Alcaide, Alex Cordero, Patricia G. Santamaría and Eva González-Suárez ()
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Ana Sofia Rocha: IDIBELL
Alejandro Collado-Solé: Spanish National Cancer Research Center (CNIO)
Osvaldo Graña-Castro: Spanish National Cancer Research Center (CNIO)
Jaime Redondo-Pedraza: Spanish National Cancer Research Center (CNIO)
Gonzalo Soria-Alcaide: Spanish National Cancer Research Center (CNIO)
Alex Cordero: IDIBELL
Patricia G. Santamaría: Spanish National Cancer Research Center (CNIO)
Eva González-Suárez: IDIBELL

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Rank signaling pathway regulates mammary gland homeostasis and epithelial cell differentiation. Although Rank receptor is expressed by basal cells and luminal progenitors, its role in each individual cell lineage remains unclear. By combining temporal/lineage specific Rank genetic deletion with lineage tracing techniques, we found that loss of luminal Rank reduces the luminal progenitor pool and leads to aberrant alveolar-like differentiation with high protein translation capacity in virgin mammary glands. These Rank-deleted luminal cells are unable to expand during the first pregnancy, leading to lactation failure and impairment of protein synthesis potential in the parous stage. The unfit parous Rank-deleted luminal cells in the alveoli are progressively replaced by Rank-proficient cells early during the second pregnancy, thereby restoring lactation. Transcriptomic analysis and functional assays point to the awakening of basal bipotency after pregnancy by the induction of Rank/NF-κB signaling in basal parous cell to restore lactation and tissue homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-41741-5

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