Interaction of plasma membrane ARF6 with JIP3/JIP4 effectors on MT1-MMP endosomes coordinates dynactin–dynein and kinesin-1 activity in a tug-of-war mechanism for endosome tubulation and MT1-MMP exocytosis to promote breast cancer cell invasion.

The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.

Purpose: High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.Experimental Design: We assessed stromal TIL levels in 716 pre-and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P ¼ 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (P Interaction ¼ 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P ¼ 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r ¼ À0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; P ¼ 0.001), but not in luminal tumors or TNBCs (P Interaction ¼ 0.04).Conclusions: The associations of pre-and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre-or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.