Page 37 - SDIR5 Abstract book 21 12 2021.

IMAGING IN CANCER

Short talks

Characterizing the role of 4E-BP1 in breast cancer metastasis

1,2
1,2
1,3
Predrag Jovanović , Sophie Guénin , Stephanie Totten , Josie Ursini-Siegel 1,2,3,4 , Ivan Topisirović 1,2,3,4
1 Jewish General Hospital, Lady Davis Institute, Montreal, Canada
2 McGill University, Experimental Medicine, Montreal, Canada
3 McGill University, Biochemistry, Montreal, Canada
4 McGill University, Oncology, Montreal, Canada

Metastasis is the leading cause of death among breast cancer patients. The multi-step process of metastasis
is intricate and still poorly understood. However, it is recognized to be a highly inefficient and strenuous
process for a cancer cell. mRNA translation, which rapidly and reversibly perturbs the proteome, is thought
to play a major role in response to cellular stress during metastatic dissemination. Specifically, eukaryotic
translation initiation factor 4E (eIF4E) binding proteins (4E-BPs) play a major role in translational regulation
by impeding the assembly of the eIF4F complex that recruits mRNA to the ribosome. In mammals, 4E-BPs
are represented by a family of three members, 4E-BP1, 2, and 3. Although literature has supported the role
of eIF4E in promoting breast cancer progression and metastasis, the role of the 4E-BPs in this process is
less understood. We demonstrate that the germline loss of 4E-BP1/2 significantly reduces lung metastases
in a mouse model of metastatic breast cancer, without impacting the growth of the primary tumors. To
dissect the mechanism, we reconstituted 4E-BP1 expression in 4E-BP1/2-deficient breast cancer cells.
Restoring 4E-BP1 expression in 4E-BP1/2 null cells promoted spontaneous metastasis of breast cancer cells
to the lung from the primary tumor site, using an orthotopic injection model. In turn, 4E-BP1 re-expression
had no effect on lung colonization and metastatic outgrowth in a tail vein injection model. Our findings
suggest that 4E-BP1 is specifically necessary for the early steps of the metastatic cascade, including
invasion, intravasation and/or survival in the blood stream.

Keywords: 4E-BP1, breast cancer, metastasis, mRNA translation

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