Early Exposure to Elevated IGF-1 Levels Increases Mammary Tumor Susceptibility through Expansion and Activation of the Mammary Stem Cell Compartment

Presentation Number: OR18-6
Date of Presentation: April 2nd, 2017

Linjie Luo*1, Andres Santos1, Andrew Hillhouse2, Kranti Konganti2, Ramesh T Gunaratna1, David Threadgill2 and Robin S L Fuchs-Young3
1Texas A&M Health Science Center, College Station, TX, 2Texas A&M University, College Station, TX, 3Texas A&M University Health Science Center, College Station, TX

Abstract

Abstract: Breast cancer (BrCa) is the most common cancer in women. Despite substantial research, BrCa incidence continues to rise, and outcome disparities persist. African American (AA) women suffer higher mortality than White women of European descent. Assessment of this disparity reveals that AA women are more likely to develop the early onset, treatment refractory, triple negative (basal) BrCa subtype associated with worse prognosis. The mechanistic basis for the difference in development of BrCa subtypes remains unresolved, but it has been shown that young AA girls have significantly higher circulating levels of Insulin-like growth factor 1 (IGF-1) than their age-matched White counterparts, implicating early exposures to this mitogenic and pro-tumorigenic growth factor in mediating BrCa subtype. To investigate the role of IGF-1 in mammary tumorigenesis, we use the transgenic (Tg) BK5.IGF-1 model, which recapitulates the paracrine effects of IGF-1 exposure on the mammary epithelium. We previously showed that exposure to elevated levels of IGF-1 are strongly pro-tumorigenic in the mammary gland, and pre-pubertal Tg mice have an increased number of terminal end buds, which are known to be important stem cell niches. In this study, we found that the mammary stem cell (MaSC) pool was expanded in both pre- and post-pubertal Tg mice compared to age-matched WT animals. Flow cytometry and immunolocalization identified the expression of IGF-1R on both WT and Tg MaSCs. Single-cell transcriptomic analysis of MaSC compartment revealed that IGF-1 stimulated Cyclin D1 (Ccnd1) gene expression and increased the proliferation of "activated" transient stem cells (T-MaSCs). Moreover, Gene Set Enrichment Analysis (GSEA) demonstrated that genes involved in stemness, proliferation, EMT, invasion and metastasis were highly upregulated in T-MaSCs from Tg mice compared to age-matched WT animals. This may also reflect the program by which quiescent-stem cells undergo commitment and exit from the niche. Previous studies suggest that loss of cell polarity is associated with increased stem cell self-renewal and susceptibility to tumorigenesis [1]. Interestingly, we also demonstrated downregulation of genes associated with cell polarity in T-MaSCs from Tg animals, suggesting an increased number of stem cells undergoing symmetric cell divisions [2]. Overall, our results identify a novel tumorigenic mechanism, by which early exposure to IGF-1 expands the MaSC compartment and “primes” these cells for transformation, thereby increasing mammary tumor incidence and reducing latency.

 

Nothing to Disclose: LL, AS, AH, KK, RTG, DT, RSLF