Abstract
Semaphorin-7a (SEMA7A), best known as a neuroimmune molecule, plays a diverse role in many cellular processes and pathologies. Here, we show that SEMA7A promotes anoikis resistance in cultured mammary epithelial cells through integrins and activation of pro-survival kinase AKT, which led us to investigate a role for SEMA7A during postpartum mammary gland involution—a normal developmental process where cells die by anoikis. Our results reveal that SEMA7A is expressed on live mammary epithelial cells during involution, that SEMA7A expression is primarily observed in α6-integrin expressing cells, and that luminal progenitor cells, specifically, are decreased in mammary glands of SEMA7A−/− mice during involution. We further identify a SEMA7A-α6/β1-integrin dependent mechanism of mammosphere formation and chemoresistance in mammary epithelial cells and suggest that this mechanism is relevant for recurrence in breast cancer patients.
Highlights
It has been postulated that the functional plasticity of the adult mammary epithelium, which is required for response to hormonal changes during pregnancy and lactation, may make the breast tissue more susceptible to malignancy.Identifying mechanisms of normal mammary epithelial cell (MEC) biology that contribute to tumorigenesis is critically important for furthering our understanding of breast cancer and extending the survival of breast cancer patients
We found that the proportion of MECs expressing SEMA7A peaks at involution day 3, marking the transition from the reversible to the irreversible phase of mammary gland remodeling
Since anoikis is one of the hallmarks of the irreversible phase of mammary involution, and our lab has published that SEMA7A overexpression in multiple breast cancer cell lines decreases anoikis and, most recently, that SEMA7A expression increases over time when cells are detached from matrix, we predicted that expression of SEMA7A would promote anoikis resistance during the second phase of irreversible involution [21, 44]
Summary
It has been postulated that the functional plasticity of the adult mammary epithelium, which is required for response to hormonal changes during pregnancy and lactation, may make the breast tissue more susceptible to malignancy.Identifying mechanisms of normal mammary epithelial cell (MEC) biology that contribute to tumorigenesis is critically important for furthering our understanding of breast cancer and extending the survival of breast cancer patients. If pups are not returned, the irreversible second phase of involution begins This phase is characterized by degradation of the mammary basement membrane by matrix metalloproteinases and anoikis-mediated cell death in the absence of laminin-mediated activation of integrin alpha-6/beta-1 (α6β1) and downstream pro-survival signaling [4,5,6]. We have identified enrichment for SEMA7A expressing α6β1 positive MECs during the matrix remodeling period of postpartum involution and a role for SEMA7A in promoting the survival of α6-integrin + luminal progenitor cells. Our results are the first to identify a role for SEMA7A in anoikis resistance and promotion of stem and cancer cell phenotypes via activation of α6 and β1-integrins. A sample of labeled cells was analyzed by flow cytometry to
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
