Differential effects of AKT1(p.E17K) expression on human mammary luminal epithelial and myoepithelial cells.

Recently, we identified a somatic mutation in AKT1, which results in a glutamic acid to lysine substitution (p.Glu17Lys or E17K). E17K mutations appear almost exclusively in breast cancers of luminal origin. Cellular models involving cell lines such as human mammary epithelial and MCF10 are model systems that upon transformation lead to rare forms of human breast cancer. Hence, we studied the effects of E17K using a clinically pertinent luminal cell line model while providing evidence to explain why E17K mutations do not occur in the mammary myoepithelium. Thus the purpose of our study was to perform a functional and differential proteomics study to assess the role of AKT1(E17K) in the development of breast cancer. We used a set of genetically matched nontumorigenic and tumorigenic mammary luminal and myoepithelial cells. We demonstrated that in myoepithelial cells, expression of E17K inhibited growth, migration, and protein synthesis compared with wild-type AKT1. In luminal cells, E17K enhanced cell survival and migration, possibly offering a selective advantage in this type of cell. However, antineoplastic effects of E17K in luminal cells, such as inhibition of growth and protein synthesis, may ultimately be associated with favorable prognosis. Our study illustrates the importance of cellular context in determining phenotypic effects of putative oncogenic mutations.

Molecular subtype analysis determines the association of advanced breast cancer in Egypt with favorable biology.

BACKGROUND: Prognostic markers and molecular breast cancer subtypes reflect underlying biological tumor behavior and are important for patient management. Compared to Western countries, women in North Africa are less likely to be prognosticated and treated based on well-characterized markers such as the estrogen receptor (ER), progesterone receptor (PR) and Her2. We conducted this study to determine the prevalence of breast cancer molecular subtypes in the North African country of Egypt as a measure of underlying biological characteristics driving tumor manifestations. METHODS: To determine molecular subtypes we characterized over 200 tumor specimens obtained from Egypt by performing ER, PR, Her2, CK5/6, EGFR and Ki67 immunohistochemistry. RESULTS: Our study demonstrated that the Luminal A subtype, associated with favorable prognosis, was found in nearly 45% of cases examined. However, the basal-like subtype, associated with poor prognosis, was found in 11% of cases. These findings are in sharp contrast to other parts of Africa in which the basal-like subtype is over-represented. CONCLUSIONS: Egyptians appear to have favorable underlying biology, albeit having advanced disease at diagnosis. These data suggest that Egyptians would largely profit from early detection of their disease. Intervention at the public health level, including education on the benefits of early detection is necessary and would likely have tremendous impact on breast cancer outcome in Egypt.