Tension-Stat3-miR-mediated metastasis

Investigator: Valerie M. Weaver, PhD
Sponsor: NIH National Cancer Institute

Location(s): United States


 In this proposal we will test the hypothesis that there is a dynamic and reciprocal relationship between chronic tissue inflammation, Stat3 and ECM tension that leads to an alteration in the expression of key microRNAs (high miR-18a, low miR-203) that induce cell proliferation, survival and invasion and promote an EMT in mammary epithelial cells to 1) promote their progression into triple-negative breast cancer and drive theirmetastatic dissemination. We contend that by identifying these tissue markers and microRNAs we will be able to 2) identify precancerous lesions that have a high likelihood of progression to triple-negative breast cancer. Our innovative mouse models and technical approaches with which we are able to manipulate and interrogate tissue tension and mechanosignaling in vivo, combined with our unique multi-institutional cohort of high risk women, including a high percentage of African American who carry a disproportionate burden of breast cancer mortality because they frequently develop triple negative breast cancer, provides us with the unprecedented opportunity to identify the earliest origins of aggressive, triple negative breast cancer so that prevention and treatment strategies can be developed.

Triple-negative breast cancers (TNBC) exhibit aggressive tumor biology and carry a poor prognosis, particularly in premenopausal African American (AA) women who carry a disproportionate burden of breast cancer mortality. The precursor lesion for TNBC is poorly characterized and the pathophysiology of TNBC is not well understood so therapies often fail to achieve complete pathological response and the disease is frequently non-curative. This proposal aims to clarify the molecular pathology of TNBC so that biomarkers for early diagnosis, prevention strategies and curative therapies can be developed. In our high-risk, multi-institutional cohort, with a high percent of AA women, we found that during breast cancer initiation, pStat3 is high as is ECM stiffness and integrin/YAP mechanosignaling, and miRNAs implicated in tumor progression/aggression. TNBCs had the highest inflammation, pStat3 and miR-18a, the stiffest ECM and the lowest miR-203. Mouse studies indicated preventing inflammation decreases fibrosis and that reducing ECM stiffening lower pStat3 and inflammation and EMT and metastasis. Driving mammary mechanosignaling induced miR-18a and EMT and enhanced tumor aggression/metastasis. This suggests that an activated Stat3/tissue tension feedback loop, linked to tissue inflammation, promotes TNBC by engaging mechanosignaling pathways that alter miRs and induce an EMT and tumor aggression. While some breast cancers arise from focal lesions, TNBCs often appear to arise diffusely. We predict that in women at high-risk for TNBC (familial association, BRCA1 mutation) there is a dynamic and reciprocal relationship between the "at risk epithelium" and tissue tension that activates mechano-signaling pathways and induces Stat3/miRNA to 
1) initiate TNBC,
2) induce an EMT and/or enhance tumor aggression, that
3) can be used to idenify precancerous lesions that have a high likelihood of progression to TNBC, and
4) could be used to monitor efficacy of prevention strategies and identify targets to improve TNBC treatment.
We will use preclinical models to test: 
1) if there is a reciprocal relationship between inflammation, pStat3 and tissue tension that promotes TNBC progression/aggression and 
2) if this is mediated through miRs and EMT. We will examine a clinical cohort of high risk women who rapidly develop TNBCs to 
3) test the prevalence of this signaling circuit in biopsies from women with TNBC and determine whether these biomarkers can identify precancerous lesions that have a high likelihood of progression to TNBC. 
Significance: Our studies could transform concepts of breast cancer by demonstrating that tissue tension could molecularly-prime tissue to malignancy. Markers that identify preneoplastic changes in TNBC, that could be used to monitor efficacy of risk reduction strategies, would have a transformative impact on TNBC mortality rates and particularly AA women.