Additional Scientific Details on Breast Cancer

The Institute aims to understand cancer progression and metastasis with a focus on the crosstalk between cancer cells and the host environment.  The Institute has a long-standing interest in the role of the serine proteases and their receptors in cancer and has defined a critical role for tissue factor (TF) - the cell surface receptor and cofactor for the coagulation protease factor VIIa in angiogenesis and tumor progression. TF modulates cell behavior through a class of receptors known as protease-activated receptors (PAR). The institute is elucidating the signaling pathways downstream of TF/PAR as they relate to cancer using transgenic and transplanted cancer models. One goal is to determine whether TF and PARs can be therapeutic targets in cancer and, particularly, whether treatments can be developed that inhibit TF and/or PAR signaling rather than procoagulant function. These studies are conducted in collaboration with Wolfram Ruf at The Scripps Research Institute.

TF signaling in cancer cells involves PAR2 and integrins and has multiple=

Another interest is the role of myeloperoxidase (MPO) in breast cancer. Epidemiological studies link high MPO expression to decreased risk of recurrent breast cancer after adjuvant therapy but the underlying mechanisms are unknown. In collaboration with Wanda Reynolds at the Sanford/Burnham Medical Research Institute, Torrey Pines Institute is using transgenic mouse models of mammary tumors to understand the role of MPO in breast cancer progression and the mechanism(s) by which it may be protective.

Substantial clinical evidence indicates that obesity is a risk factor for the development of breast cancer. In fact, obesity at time of breast cancer diagnosis has a negative impact on prognosis for both premenopausal and postmenopausal women. Recently the Institute has begun to develop models to study interaction between cancer cells and adipocytes in the breast microenvironment and to ascertain the factors by which local adipocytes contribute to the development of estrogen receptor-positive as well as so-called triple-negative breast cancer.

Local adipocytes support growth of ER-positive breast cancer in a mouse model. MCF-7human breast tumors grown in F442A fat pads in SCID mice. In panels A-C fairly uniform small tumor cells have blue violet nuclei and pink cytoplasms (T: tumor). Mature adipocytes appear as empty profiles since the large central fat droplets dissolve during tissue processing (A: adipocytes). Gross morphology of a MCF-7/F442A tumor (arrow) in D.

The Institute has found that human breast cancer cells, but not normal tissue from the same breast, produce very large amounts of the type of free fatty acids that block the cytotoxic T lymphocytes (CTL).  CTL in the absence of the free fatty acids would likely destroy the cancer cells.  Thus the cancer may have a way of defending itself against attack by the immune system, thereby reducing the potential efficacy of novel anti cancer therapies that rely on a functioning immune system. Consequently, strategies that reduce the amount of fatty acids surrounding the tumors may give a boost to anti-cancer therapeutics. Details of these findings appear in the Journal of Lipid Research, 2005.

Immunotherapy of Prostate and Breast Cancer: Tumour Vascular Targeting

Currently the Institute is evaluating the therapeutic value of recently identified tumor endothelial markers as targets for tumor vascular targeting strategies. We are currently focusing specifically on prostate and breast cancer. To this end we developed dendritic cell-based vaccines composed of autologous dendritic cell pulsed ex vivo with tumor endothelial marker(s) of interest. The vaccines are currently tested in vivo in pre-clinical animal models that mimic closely the disease in human such TRAMP mice (Transgenic Adenocarcinoma of the Mouse Prostate) for prostate cancer and the transgenic mice Her-2neu for breast cancer. If the vaccines are effective and non toxic in the pre-clinical models, it can be brought to clinical trials. Our goal is to develop novel, well tolerated, effective vaccines for prostate and breast cancer that will reduce the need for chemotherapy, improve patients’ quality of life, and prolong survival.