Local Adipocyte Function in Breast Cancer

Institution: Torrey Pines Institute for Molecular Studies
Investigator(s): Barbara Mueller, Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16IB-0032 Award: $272,993
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2010)

The importance of the local microenvironment in breast cancer growth and progression is becoming increasingly clear. Adipocytes (fat cells) are abundant in the mammary microenvironment, and recent studies show that adipocytes produce a multitude of endocrine, inflammatory, and angiogenic factors that have tremendous potential to affect adjacent breast cancer cells. In spite of this, the extent to which local adipocyte function contributes to the pathogenesis of breast cancer is largely unexplored.

We plan to develop a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment. First, we will determine whether fat pads derived from subcutaneous injection of murine pre-adipocytes into mice will support the growth of human MCF-7 and T47D breast cancer cells lines in the absence of estrogen supplementation. We will also test whether transplanted fat supports breast cancer growth and whether fat from lean and obese mice differs in its ability to support tumor growth. We will also assess the contribution of local and distant pads and transplanted fat pads by injecting breast cancer cells either into the fat or the opposite side of the mouse. Next, we will determine the effect of recombinant leptin (i.e., a hormone that has a central role in fat metabolism) and a leptin receptor antagonist on aromatase RNA and protein expression and on aromatase activity in mouse and human adipocytes in cell culture and in fat pads in mice. We will test the contribution of local adipocyte aromatase activity to hormone-dependent breast cancer growth in mice using aromatase substrate androstenedione and the aromatase inhibitor anastrozole (Arimidex). The role of local leptin production will be determined by transplanting fat from leptin-deficient mice.

The development of a specific mouse model to study interactions between adipocytes and breast cancer in the tumor microenvironment has the potential to impact several important areas in breast cancer research. First, our work will clarify the importance of local adipocytes in hormone-dependent breast cancer, demonstrate a role for local aromatase activity, and identify the leptin-aromatase axis as a target for prevention or neoadjuvant therapy. Secondly, our studies will provide a means to assess the contribution of adipocytes to increased breast cancer risk and poor breast cancer prognosis in obese women. Finally, it will enable the study of local adipocyte function in the growth and progression of different types of breast cancer, including HER2-positive breast cancer and triple-negative breast cancer.

Final Report (2011)

Obesity is a risk factor for the development of breast cancer. Given the fact that obesity has now reached epidemic proportions in the US, understanding the mechanism of how obesity affects mammary tumorigenesis is an important health issue. Obesity leads to a dysfunctional adipose tissue and alters secretion of various factors from the adipose tissue, which can affect mammary carcinogenesis and tumor progression. Increasing evidence also supports the concept that cancer cells cannot develop into lethal tumors without the cooperation of other neighboring cells. A cell type that is abundant in human breast tissue is the fat cell, also known as adipocyte. Fat cells increase in number and size in obesity and adipose expansion in obesity is associated with pathological changes in tissue remodeling and inflammation. In spite of this, the contribution of fat cells in the breast microenvironment is largely unexplored. We believe that this is in part because of the lack of suitable experimental animal models.

The objective of this proposal is to develop a mouse model to directly study interactions between fat cells and hormone-dependent breast cancer cells. We have now demonstrated that hormone-dependent human breast cancer cells, which are not tumorigenic when injected into mice by themselves, grow tumors when they are inoculated together with fat cells. Importantly fat cells are only able to support tumor growth when they are in direct contact with the breast cancer cells and not when they are at a distant side of the same mouse. This suggests that fat cells produce locally acting factors, not factors that are secreted into the blood and distributed to a distant side. We have proposed that local production of estrogen by the enzyme aromatase -which in turn is upregulated by the fat cell hormone leptin - is critically important. Consistent with that idea we have demonstrated the upregulation of aromatase by leptin in fat cells. However, administration of an aromatase inhibitor in mice did not impede tumor growth. The role of aromatase in vivo needs to be studied using additional approaches and we also will consider the possibility that specific adipocyte-produced growth factors can overcome estrogen-dependence.

Local adipocytes enable estrogen-dependent breast cancer growth
Index Medicus: Adipocyte
Authors: Enbo Liu, Fahumiya Samad, and Barbara M Mueller
Yr: 2013 Vol: July Nbr: 3 Abs: Pg:165-169