Alveolar progenitor cells in the mammary gland are dependent on the β4 integrin

Walker, Melanie R.; Amante, John J.; Li, Jiarong; Li, Haibo; Zhu, Lihua Julie; Feltri, M. Laura; Goel, Hira Lal; Mercurio, Arthur M.

doi:10.1016/j.ydbio.2019.10.001

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…We discovered that Lama5 is predominantly expressed in the HR + luminal epithelial cells, and when Lama5 was deleted in the luminal cells at various stages, we found that it has a critical role during pubertal growth and pregnancy-induced remodeling and growth. Our results are in concert with previous studies showing that the downregulation of laminin-binding adhesion receptors, including β1- and β4-integrins, results in the inhibition of mammary epithelial growth and alveologenesis ( Li et al, 2005 ; Naylor et al, 2005 ; Walker et al, 2020 ; Romagnoli et al, 2020 ). Together, these data underline the importance of laminin and BM microenvironment in the regulation of mammary epithelial growth and differentiation.…”

Section: Discussionsupporting

confidence: 91%

Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk

et al. 2021

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Epithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we show that Laminin α5 (Lama5) expression specifically in the luminal epithelial cells is necessary for normal mammary gland growth during puberty, and for alveologenesis during pregnancy. Lama5 loss in the keratin 8-expressing cells results in reduced frequency and differentiation of hormone receptor expressing (HR+) luminal cells. Consequently, Wnt4-mediated crosstalk between HR+ luminal cells and basal epithelial cells is compromised during gland remodeling, and results in defective epithelial growth. The effects of Lama5 deletion on gland growth and branching can be rescued by Wnt4 supplementation in the in vitro model of branching morphogenesis. Our results reveal a surprising role for BM-protein expression in the luminal mammary epithelial cells, and highlight the function of Lama5 in mammary gland remodeling and luminal differentiation.

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Section: Discussionsupporting

confidence: 91%

Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk

et al. 2021

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“…Indeed, unlike α3, α6 can associate with β4 and the α6β4 dimer, unlike β1-containing integrins, is a component of hemidesmosomes. A recent study reported that deletion of β4 integrin from luminal cells induced defects in alveologenesis and milk production during pregnancy (Walker et al, 2020). Thus, the decreased β4-integrin surface levels detected in α3α6KO luminal cells could contribute to the observed phenotype.…”

Section: Discussionmentioning

confidence: 95%

Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation

et al. 2020

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Integrin dimers α3/β1, α6/β1 and α6/β4 are the mammary epithelial cell receptors for laminins, which are major components of the mammary basement membrane. The roles of specific basement membrane components and their integrin receptors in the regulation of functional gland development have not been analyzed in detail. To investigate the functions of laminin-binding integrins, we obtained mutant mice with mammary luminal cell-specific deficiencies of the α3 and α6 integrin chains generated by the Cre-Lox approach. During pregnancy, mutant mice displayed decreased luminal progenitor activity and retarded lobulo-alveolar development. Mammary glands appeared functional at the onset of lactation in mutant mice, however myoepithelial cell morphology was markedly altered, suggesting cellular compensation mechanisms involving cytoskeleton reorganization. Notably, lactation was not sustained in mutant females, and the glands underwent precocious involution. Inactivation of the p53 gene rescued the growth defects but did not restore lactogenesis in mutant mice. These results suggest that the p53 pathway is involved in the control of mammary cell proliferation and survival downstream of lamininbinding integrins and underline an essential role of cell interactions with laminin for lactogenic differentiation.

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“…2c). Moreover, 18m P basal cells had increased expression of milk-protein genes, such as Csn1s1 and Csn2, suggesting that basal cells upregulate pathways of milk-production during pregnancy or give rise to milk producing cells 26 , or vice versa 27 . We also detected a modest down regulation of genes associated with stem/progenitor cells (Tspan8 and Bcl11b) 28,29 and growth factor receptors (Erbb3 and Egr2).…”

Section: B)mentioning

confidence: 99%

Pregnancy Reduces Il33+ Hybrid Progenitor Accumulation in the Aged Mammary Gland

Olander,

Ramirez,

Acosta

et al. 2024

Preprint

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Aging increases breast cancer risk while an early first pregnancy reduces a woman’s life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary epithelial cells (MECs), but the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population ofIl33-expressing hybrid MECs with high cellular potency that accumulate in aged nulliparous mice but is significantly reduced in aged parous mice. Functionally, IL33 treatment of basal, but not luminal, epithelial cells from young mice phenocopies aged nulliparous MECs and promotes formation of organoids withTrp53knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated loss of lineage integrity in the basal layer through a decrease inIl33+hybrid MECs, potentially contributing to pregnancy-induced breast cancer protection.

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Alveolar progenitor cells in the mammary gland are dependent on the β4 integrin

Cited by 6 publications

References 20 publications

Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk

Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk

Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation

Pregnancy Reduces Il33+ Hybrid Progenitor Accumulation in the Aged Mammary Gland

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