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Metastasis stage (Steeg) Invasion and motility
Hanahan/Weinberg Activating invasion & metastasis
Understanding (basic)
Research stage
Translational
Pathway n/a
Therapy/intervention diagnostic/prognostic/research tool
A grant with a focus on Metastatic colonization
Title:
Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and
Therapeutic Decision Making
Background: Most of the morbidity and mortality from breast cancer stems from the failure to adequately control metastases using
existing chemotherapies. Metastatic colonization of secondary sites is an important rate-limiting step in the progression of metastatic
disease. The role of the cell adhesion molecule E-cadherin in initiating tumor invasion and dissemination is well-established. However,
recent findings of E-cadherin expression in metastatic foci originating from E-cadherin-negative primary tumors suggest that E-cadherin
re-expression may play a role in metastatic colonization. In fact, our laboratory has found that co-culture of E-cadherin-negative
metastatic breast cancer cells with hepatocytes induces E-cadherin re-expression and that these induced adhesion molecules can
bind with those on hepatocytes to activate the canonical ERK and Akt cell survival pathways. Objective/Hypothesis: We will test the
hypothesis that metastatic breast carcinoma cells require E-cadherin re-expression to integrate and subsequently to confer a survival
advantage in the liver, a common site of breast cancer metastases. Specific Aims: (1) Determine whether breast cancer cells upregulate
E-cadherin expression within a metastatic niche. (2) Determine whether E-cadherin re-expression endows resistance to chemotherapy.
Impact: This proposal aims to fill a gap in our understanding of the pathogenesis of breast cancer metastasis. The molecular basis of
metastatic progression is still poorly understood, and not much is known or being studied about metastases to the liver. The work in the
proposal is relevant because it not only advances what is currently known about metastasis, but also identifies a putative target that can
be used clinically. Further, the skills learned under this training award can be directly applied to investigating other molecules of interest
believed to be involved in cancer progression.
Metastasis stage (Steeg) Metastatic colonizationy
Hanahan/Weinberg Activating invasion & metastasis
Research stage Understanding (basic)
Pathway E-cadherin
Therapy/intervention n/a
A grant with a focus on Immune surveillance/escape
Title:
Blocking breast cancer cell Type I IFN signalling prevents immune recognition and allows metastatic progression to bone.
Breast cancer is rarely curable once it has spread to bone. Our recent studies have revealed that cancer cells growing in bone suppress
an immune defence pathway called the Type I interferon (IFN) pathway, and that restoration of this pathway blocks cancer spread. In this
project, I aim to identify the immune responses that are specifically activated when cancer cells produce Type I IFN and test if restoration
of such responses is critical in blocking the spread of breast cancer to bone. This project will reveal the role of the Type I IFN immune
pathway in activating the immune system and preventing breast cancer spread and may discover new therapeutic avenues for treating
advanced breast cancer patients.
Metastasis stage (Steeg) Immune surveillance/escape
Activating invasion & metastasis
Hanahan/Weinberg
Avoiding Immune Destruction
Research stage Understanding (basic)
Pathway Type I IFN
Therapy/intervention n/a
