Nfatc1's Role in Mammary Epithelial Morphogenesis and Basal Stem/progenitor Cell Self-renewal.

Mammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary gland fuel the morphogenesis and regeneration of a complex epithelial network during development and upon transplantation. The self-renewal of basal stem/progenitor cells is subjected to regulation by both cell-intrinsic and extrinsic mechanisms. Nfatc1 is a transcription factor that regulates breast tumorigenesis and metastasis, but its role in mammary epithelial development and stem cell function has not been investigated. Here we show that Nfatc1 is expressed in a small subset of mammary basal epithelial cells and its epithelial-specific deletion results in mild defects in side branching and basal-luminal cell balance. Moreover, Nfatc1-deficient basal cells exhibit reduced colony forming ability in vitro and somewhat compromised regenerative potential upon transplantation. Thus, our study provides evidence for a detectable yet non-essential role of Nfatc1 in mammary epithelial morphogenesis and basal stem/progenitor cell self-renewal.

Bisphosphonate-associated arthritis.

We present a case of arthritis apparently induced by the administration of intravenous bisphosphonates in a 51-year-old white woman with metastatic breast carcinoma. She presented with bilateral knee pain and effusions on 2 separate occasions after receiving aminobisphosphonates. Synovial fluid analysis was negative for infection, metastasis, or crystals. Her symptoms resolved after the medication was discontinued and recurred after the patient was rechallenged with a medication from the same drug class. The administration of aminobisphosphonates has been associated with an acute-phase response in several in vivo studies. The mechanism of action is thought to be that aminobisphosphonates transiently stimulate the production of proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha. Rheumatologists should be aware of this possible cause of arthropathy.