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    Research Grants Awarded

    Collagen receptors as novel targets to lower the breast cancer risk associated with high mammographic density

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    Background: The association between increased breast density and the risk of developing breast cancer was discovered 30 years ago. These findings were confirmed by a multitude of subsequent studies, indicating that high mammographic density correlates with a four-fold or greater risk for breast cancer. Surprisingly however, the biological basis of this connection is, as yet, completely unknown. Studies on biopsy tissue found that high radiographic density is caused by increased collagen deposition as well as elevated cellularity. This suggests that aberrant interactions between mammary cells and the surrounding collagenous stroma lead to a higher risk of cancer. Rational and hypothesis: Our previous work has revealed that the tyrosine kinase receptors Discoidin Domain Receptor (DDR) 1 and 2 are activated by native collagens. Using a variety of normal and transformed breast cells, we observed that DDR activation by collagen results in sustained tyrosine kinase signaling function. Importantly, knockout mice lacking DDR1 fail to develop normal mammary gland epithelia at puberty and are unable to lactate at parturition. DDR1 is expressed by luminal epithelial cells and regulates adherens junction assembly, while DDR2 is found in the mammary stroma. In the current proposal we will test the hypothesis that aberrant DDR expression and signaling can cause the increased breast density linked to higher cancer risks. In the first aim we will explore this, in vitro, by analyzing DDR expression and signaling in three-dimensional tissue culture assays stimulated with altered collagen concentrations. In the second aim, we will use advanced microscopy techniques, such as polarized light birefringence, to investigate whether an altered collagen structure may lead to differential cellular growth, modeling changes in breast density. Furthermore, we will use genetically or enzymatically modified collagen preparations to unravel the specific extracellular matrix signals that trigger mammary epithelial cell proliferation and transformation. These findings will be validated in the third aim using mouse models. We will implant DDR1-null and wild-type mammary epithelial cells into the cleared fat-pad of recipient mice together with various types and concentrations of collagen. X-ray and whole-mount techniques will be used to analyze density, morphology and cellularity of the transplanted mammary glands. Relevance: Our research aims to unravel the so far mysterious mechanism linking breast density to elevated cancer risk. The proposed research will lead to the identification of collagen-mediated DDR signaling mechanisms that control breast tissue composition and tumor promotion. Our work will be relevant to the large target population of women with high breast densities. We anticipate that cell surface receptor interfering drugs may potentially qualify as preventative measures to reduce breast density and the associated cancer risk in healthy women.

    Lay Abstract:
    Background: Exactly thirty years ago, a radiologist discovered a link between elevated breast tissue density and an increased risk for the development of breast cancer. In the past years, many follow-up studies confirmed that high density correlates with a four-fold higher risk for the development of breast cancer. Higher breast density is due to a higher percentage of fibrous tissue relative to fat tissue in the mammary gland. Approximately 25% of postmenopausal women have higher than normal breast densities, exposing a large number of individuals to a potential cancer risk. Strikingly though, the biological basis of this association is completely unknown. It is clear, however, that collagen is one of the most common components of dense breast tissue. We, and others, have proposed that collagen is involved in the progression of breast cancer. Rationale and hypothesis: Our previous work has revealed that two surface molecules in normal breast cells, that we named Discoidin Domain Receptors (DDR), are activated by collagens. Using a variety of normal cells and breast cancer cells, we observed that DDR activity is necessary for the maintenance of normal breast function. Mice lacking DDR have abnormal mammary gland function, and are unable to lactate after giving birth. In the current proposal we will test the hypothesis that abnormal DDR function is linked to increased breast density and thereby to a higher risk for cancer. In the first aim we will explore this by testing DDR function in three-dimensional tissue culture assays containing collagen. We will use well-established DDR expressing breast cancer cell lines and record their signaling activities within a collagen-rich environment. In the second aim, we will use advanced microscopy techniques to investigate whether an altered collagen structure is the link between higher breast density and cancer risk. Furthermore, we will use genetically or chemically modified collagen preparations to unravel the signals that might trigger cancerous growth of breast tissue cells. These findings will be confirmed in the third aim using whole animals. We will use X-ray and tissue staining techniques to analyze breast density and cell counts of mice with both altered DDR function and elevated mammary gland collagen deposition. Relevance: Our research aims to solve the, so far mysterious, mechanism that links breast density to elevated cancer risk. Our work will identify collagen-mediated DDR signals that control breast tissue composition and tumor promotion. Targeting DDR with inhibitors may lower breast density and therefore cancer risk in postmenopausal women. We believe that by better understanding the many subtle mechanisms that lead to breast cancer, we will be able to fight it.