Abstract 15: Inhibition of IGF-1 suppress genomic instability and epithelial lineage aberrations in the mammary gland of BRCA1 deficient mice
Authors: Ignacio Fernandez-Garcia, Pietro Ameri, Mary Helen Barcellos-Hoff, David L. Kleinberg
Journal: Cancer Research (2012)

Abstract Women carriers of mutations in the tumor suppressor gene, BRCA1, have an up to 80% risk of developing breast cancer, as well as a 40% risk of ovarian cancer. Men who develop breast cancer are frequently BRCA1 mutation carriers. Moreover, cancers associated with BRCA1 mutations are frequently triple-negative (negative for estrogen receptor, progesterone receptor and HER2 amplification), which have a very poor prognosis. Experimental data have shown that BRCA1 has a dual role in the mammary epithelium in both DNA damage repair and in epithelial lineage commitment that contribute to the high frequency of triple-negative breast cancer. Brca1 deficiency in experimental models is also associated with increased phosphorylation of the IGF-1 receptor which in turns, leads to the MAPK signaling activation and results in increased proliferation. We evaluated a novel IGF-1 inhibitor in the Brca1 loxP/loxP C57bl/6 mouse that develops an early mammary gland hyper-proliferative phenotype characterized by aberrant ductal morphogenesis and DCIS around 9 months of age. Centrosome aberrations, defined cells with more than 2 centrosomes, were significantly increased the mammary epithelium of these mice compared to C57bl/6 control mice (19.8%±0.8%, n=13 vs 8.4%±0.9%, n=6, p&amp;lt;0.001). We also identified a novel population of cells expressing both a luminal and myoepithelial lineage markers present in the Brca1 loxP/loxP C57bl/6 mice that were rare in control mice (22.5%±0.9%, n=5 vs 3.9%±0.4%, n=7, p&amp;lt;0.001). Four month old Brca1 loxP/loxP and C57bl/6 mice were treated with either pasireotide (aka SOM230), a multiligand somatostatin analog that directly blocks IGF-1 action in the mammary gland or PQ401, a IGF-IR small molecule inhibitor, administered for 7 days by subcutaneous Alzet pumps Pasireotide and PQ401 inhibited IGF-1 mediated phosphorylation of target proteins, IGF-IR, ERK and AKT in the Brca1 mammary glands. Both treatments resulted in rapid reversion of the Brca1 mutant gross morphological phenotype. Remarkably, inhibiting IGF-I action also rescued the abnormal composition of the epithelium. The frequency centrosome aberration was significantly reduced (9.3%±1.6%, n=6, p=0.01) by pasireotide. Moreover, the frequency of atypical cells expressing both luminal and myoepithelial markers was significantly decreased (4.8%±1.3%, n=2, p&amp;lt;0.001). Thus IGF-1 inhibition not only normalizes the tissue architecture of Brca1 deficient mammary gland, but also eliminates aberrant cells that are likely susceptible to malignant transformation. In summary, these results open the possibility of normalizing the breast epithelium through the inhibition of IGF-1 in women who have BRCA1 mutations. Supported by DOD-BCRP IDEA Expansion award. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 15. doi:1538-7445.AM2012-15