BRCA1 signaling pathways in determining stem and progenitor cell fate

Amina Khimani

Introduction. Breast Cancer is the most common cancer among women worldwide1. Approximately 5-10% of breast cancers are hereditary, and mutations in the BRCA1 gene prove to be the most prevalent in terms of genetic susceptibility2. The BRCA1 gene exhibits an important role as a tumor suppressor, with special functions in DNA repair. Essentially, BRCA1 helps in the maintenance of genomic stability3. Currently, treatment options are quite limited for these patients. In order to help prevent and treat these tumors, studies are focused on understanding the progression of breast cancer, and the biological mechanisms that initiate these tumors. Thus far, in vitro and in vivo models have shown that Rel B and p100/52 are activated in human BRCA1-mutation carriers, as well as BRCA1-deficient mouse mammary progenitor cells. These models have shown that NF-κB activation stimulates progenitor and stem cell expansion, as well as inhibits differentiation4. These findings could suggest a potential target for treatment in patients with the BRCA1 mutation. Methods. BRCA1 was knocked down on three different cell lines: human nontumorigenic, luminal, and basal subtype. Immunofluorescence analysis was then performed to detect NF-κB components p100/52 and RelB. An in-vivo mouse model was also used, and immunofluorescence analysis conducted. To detect ALDH1 (a stem/progenitor cell marker) immunofluorescence was performed in 3 BRCA1 mutation carriers, and BRCA1 wildtype carriers. Mouse mammary epithelial cell line was transfected with an empty vector, or a p52-expressing vector, and differentiation was assessed by microscopy4. Results. BRCA1 loss or mutation induces the alternative NF-κB pathway in vitro and in vivo. Immunofluorescence studies proved that the pathway is constitutively active in BRCA-1 deficient mammary progenitor cells, and that DNA damage activates the alternative NF-κB pathway5. The alternative NF-κB pathway activation then induces stem/progenitor cell proliferation and blocks their differentiation. In a similar study, it was shown that a subset of mammary gland sections from patients with a BRCA1 mutation contained whole histologically normal lobular units that over express the stem/progenitor cell marker ALDH1; therefore, ALDH1 positive cells represent the expanded progenitor cell population within these glands. Lastly, studies show that when NF-κB is overexpressed, differentiation is inhibited4. Conclusion. BRCA1 mutation carriers and BRCA1-deficient mouse mammary glands contained a population of mammary luminal progenitors that can form colonies without the presence of hormones. Proliferation of these cells and inhibition of differentiation can occur through the activation of the alternative NF-κB pathway. An NF-κB pathway directed therapeutic may provide a novel alternative to prophylactic mastectomy in this high risk patient population.

 

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