Stromal-Epithelial Interactions during Breast Cancer Development

The initiating events in breast cancer development have typically been thought to occur in the mammary epithelial cells. Tumorigenesis progresses through a selective mechanism whereby a normal mammary epithelial cell acquires specific growth promoting advantages and transforming characteristics. However, the mammary gland is a complex tissue, which does not exist as a homogeneous population of cells responding synchronously to its environment. Rather, the mammary epithelium is embedded in a vast array of stromal cells that regulate its proliferation, differentiation, and survival. The breast is also under the control of various endocrine hormones. Therefore, for mammary epithelium to progress towards a malignant state, the surrounding stroma must either actively stimulate or preferentially select the population of cells that are progressing towards transformation.

Our lab utilized a novel human breast xenograft model system to study the various genetic and epigenetic interactions involved in various aspects of normal and neoplastic breast development. We are examining a number of genes for their respective abilities to cause normal mammary epithelial cells to generate abnormal structures that are associated with the various stages of human breast cancer progression including Her2, ras, cyclin D1, c-myc, or loss of p53 or BRCA1.

An additional extension of this work involves determining the role of the stromal fibroblasts as tumor promoters or suppressors in the development of breast carcinomas. To do this, we will take advantage of the humanized stromal environment to genetically modify the stromal cells with various factors.

Metastasis

Invasive and metastatic breast cancer is associated with a high degree of morbidity and mortality in women and metastasis to bone is the leading cause of such effects and it is observed in 65%-80% of autopsies from women who have died of this disease. The propensity with which breast cancer associates with bone in advanced stages of malignancy suggests a molecular basis for this attraction. The majority of bone lesions associated with breast cancer metastases are osteolytic, and involve mobilization of osteoclasts from the bone tissue's inherent resorption machinery. In this process, it is thought that breast cancer cells secrete factors that act in a paracrine fashion to activate the latent osteoclasts within the bone tissue, leading to the degradation of the mineralized bone. This causes the release of specific growth factors and cytokines that were previously embedded within the bone matrix during the process of bone formation. These liberated growth factors act in turn back on the breast cancer cells themselves to promote their growth and proliferation. Given what is known about this "vicious cycle" of tumor osteolysis in skeletal metastases, the actual cells in the primary tumor which seed and survive in the bone marrow, and the subsequent signals that trigger the cells to proliferate remain unclear.

Using several in vivo mouse xenograft models, our lab is interested in identifying the cellular elements (cell types, growth factors, matrix proteins) in the bone stroma can promote the tumor formation in the distant site. Using other established in vivo approaches we are also interested in determining whether which cells in a tumor mass are in fact metastatic and establishing their fate (i.e. differentiation, proliferation, etc.) when they enter specific tissue environments such as lung, liver or bone marrow. More importantly, we would like to determine how that environment either promotes or suppresses the metastatic outgrowth of the cancer cells.

Systemic Effects on Breast Cancer Development

The life-time risk of developing breast cancer is reduced by nearly 50% after one full term pregnancy, yet women over the age of 25 have a significantly greater risk of developing breast cancer than their nulliparous counterparts following parturition. The underlying mechanism of this dual effect of parity on breast cancer risk still remains unclear. Our lab is examining the possibility that the tumor-promoting effects following parturition may be occurring through local or systemic mechanisms that promote the further proliferation of an already-initiated target cell population that was present in the breast prior to pregnancy, with an emphasis on the cell types present in the bone marrow and circulation during this phase of development. We would like to extend the studies to determine which hormones during pregnancy/lactation are responsible for increased numbers of cells in the bone marrow and if these progenitor cells are then released into the circulation, and help promote the angiogenesis of initiated cancer cells