poster abstractLi-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutations in
the tumor suppressor gene TP53. Breast cancer (BC) is the most common tumor amongst women with
LFS, who have increased risk for premenopausal BC before age 40 and a lifetime risk of 49% by the age
of 60. Non-malignant, human mammary epithelial cells (HMECs) were derived from the contralateral
breast tissue of LFS patient (LFS50) undergoing BC surgery. The LFS50 HMEC progression series
comprises of pre-immortal (HME50), spontaneously immortalized (HME50-5E), hTERT-immortalized
(HME50hTERT or HME50hT), and tumorigenic (HMET) which can be modeled to represent breast
cancer progression. Gene expressions of the LFS50 series were profiled using HG-U133_Plus_2
Affymetrix chip. By hierarchical clustering, the LFS50 cells were observed to have significant differential
expression of genes and ANOVA results revealed that EMT-related genes (e.g., epithelial membrane
protein 3, p= 6.84911E-19; E-cadherin, p= 8.66098E-19; and Keratin 5, p= 9.73095E-19) to be the most
differentially expressed amongst the LFS50 cells. Ingenuity Pathway Analysis (IPA) confirmed that Ecadherin
and Keratin 5 were the top most differentially expressed genes as well as G2/M DNA Damage
Checkpoint Regulation (p= 2.67E-05), Estrogen-mediated S-phase Entry (p=3.32E-04) Mitotic Roles of
Polo-Like Kinase (p=5.5E-04) as few of the top canonical pathways. Furthermore, to identify the type of
breast cancer that LFS50 series could model, the triple negative breast cancer (TNBC) subtyping database
tool predicted that each of the LFS50 strains could be classified as a different subtype. Finally, as a proof
of principle for drug targeting, treatment of the LFS50 series with PRIMA-1, a p53 rescue drug, using 3D
cultures resulted in a reduction in acini size of the pre-invasive LFS50 cells (p<0.05). Therefore, this
progression series can serve as a resource for drug target discovery and breast cancer prevention research
