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"Obesity, Type 2 diabetes and the increased risk of cancer and cancer-related Mortality; the study of Molecular Mechanisms and potential therapeutic modalities."

Final Report Summary - DIABESITY (Obesity, Type 2 diabetes and the increased risk of cancer and cancer-related Mortality; the study of Molecular Mechanisms and potential therapeutic modalities.)

The following specific aims were addressed in the research over the period of the grant.
Specific Aims
1. To determine if the hyperinsulinemia in female MKR mice affects mammary tumor development and metastases to the lungs.
The hyperinsulinemic MKR mice had orthotopic of mouse mammary cancer cells injected into the 4th mammary gland. Compared to wild type control mice the tumors grew more rapidly and there was increased lung metastases in the MKR mice. When cancer cells were injected into the tail vein there was similarly an increase in lung metastases, suggesting that the metastases was dependent on the hyperinsulinemia and not necessarily the size of the primary mammary gland tumors.
We have developed cancer cell lines with knockdown (KD) of the insulin (IR) and IGF-1R using shRNA technology and implanted these cells into the mammary gland of the MKR mice. The IR-KD tumors grew slower (and had fewer metastases) compared to IGF-1R-KD and control tumors, supporting the conclusion that the IR is mediating the effect of hyperinsulinemia on mammary growth and metastases.
Tumors were examined for gene expression analysis and pathway analysis and the tumors from hyperinsulinemia mice showed a specific pattern consistent with genes involved in growth, metastases and anti-apoptosis.
We have also demonstrated that there is epithelial-mesenchymal transformation in the hyperinsulinemic tumors by demonstrating an increase in vimentin expression.

2. To determine if hypercholesterolemia in the ApoE-/- female mice affects mammary tumor development and metastases to the lungs.

apoE-/- mice are dyslipidemia with high cholesterol and high triglyceride levels.
Introducing mouse mammary tumor cells into the 4th mammary gland also led to increase primary tumor growth and more lung metastases compared with control mice.
Cell culture experiments demonstrated that LDL cholesterol stimulated cell proliferation and was inhibited by lipid raft disruption. Cellular signaling involved increased p-AKT and inhibition of p-ERK; the latter due to an increase in a phosphatase.

3. To study the effect of insulin and cholesterol on mammary epithelial cell (MEC)- and MVT1 tumor-derived stem/progenitor cells.

We have demonstrated that the MVT1 tumors used in the above experiments express a specific stem/progenitor cell marker, CD24. CD24 + cells are much more aggressive in cell culture and cause greater tumor growth in mice compared to CD24- cells. These stem cells explain the aggressiveness of the tumors in the hyperinsulinemic mice.

In summary
We have been successful in completing studies outlined in the specific aims and are continuing to pursue the studies in more depth