通过整合小鼠和人体研究表征年轻发病DCIS中的肌上皮标志物缺失

INTRODUCTION: Postpartum breast cancer (PPBC), diagnosed within 5-10 years after recent childbirth, is associated with increased metastasis, but postpartum status's impact on mortality among young women diagnosed with Ductal Carcinoma in Situ (DCIS) remains unclear. This study investigates how the postpartum environment may influence DCIS behavior in young women (≤45 years) diagnosed with DCIS and explores biological mechanisms through myoepithelial markers that could promote postpartum DCIS progression. METHODS : Young women diagnosed with DCIS and invasive breast cancer were identified through the statewide Utah Population Database (UPDB) and SEER Utah Cancer Registry data (diagnosis year 1996-2017 with a median follow-up of 12.5 years, and mortality outcomes were evaluated in relation to DCIS diagnosis time since recent childbirth. Patterns of postpartum status among women diagnosed with DCIS versus invasive breast cancer were compared. To identify underlying biological mechanisms, we examined myoepithelial integrity in normal human breast tissues collected at defined post-weaning intervals and used mouse models of DCIS to evaluate how postpartum mammary gland involution influences tumor progression. RESULTS : Of 597 women with DCIS, 23 deaths occurred during follow-up. DCIS was less frequent in the <5-year postpartum group (12.4%) compared to nulliparous (17.6%) and 5-<10 years group (17.6%), and invasive BC more frequent in the <5-year group. ER-negative DCIS was higher in the <5-year group (18%) compared to other groups (7%, 6%, 9%). Mortality outcomes were similar between postpartum and nulliparous women, with no clear evidence of increased all-cause mortality associated with recent childbirth. In normal human breast, postpartum breast involution is associated with reduced expression of the myoepithelial markers p63 and calponin, hallmarks of DCIS-to-invasive transition. Mouse models of postpartum DCIS confirmed increased tumor progression in involuting glands compared to nulliparous controls. Moreover, calponin loss in murine mammary myoepithelium correlated with increased tumor dissemination. CONCLUSION: In young onset DCIS patients, BC-specific mortality was very low during the follow-up, implicating standard care as largely curative. We observed lower frequency of DCIS in the <5-year postpartum group suggesting potential progression of DCIS to invasive carcinoma during the early postpartum period. We find that recent childbirth, specifically weaning, reduces myoepithelial cell calponin expression, potentially facilitating DCIS progression to invasive disease. Calponin loss in a DCIS mouse model confers tumor advantage. These results highlight the importance of reproductive history and the postpartum breast microenvironment in early breast cancer prognosis and may inform risk-stratified management strategies for young women with DCIS.