Using Physical Sciences Approaches to Investigate the Mineralized Microenvironments of Metastatic Breast Cancer

Abstract

Breast cancer is among the most common malignancy in women worldwide. Progress in early detection and targeted therapeutics have improved the clinical prognosis of patients with localized cancer. However, high mortality rates and short median survival times continue to be associated with skeletal metastases, which occur in 80% of patients with advanced disease. These dismal statistics reflect an inadequate mechanistic understanding of the microenvironmental factors that mediate the progression of primary breast cancer to bone metastasis. In particular, hydroxyapatite (HA) mineral, a key component of mammary calcifications and an essential nanostructural constituent of bone tissue, has largely been overlooked in studies of breast cancer, but may play an important role in its malignant progression. Thus, the overall goal of this work was to examine the relevance of HA mineral to bone metastatic disease within mineralized microenvironments specific to the breast cancer metastatic cascade. To this end, innovative, interdisciplinary approaches spanning tissue engineering, materials science, and cell biology were pursued. Chapter 2 focuses on the functional characterization of tumor cell-HA interactions and details the use of a tissue-engineered scaffold system to investigate whether HA can actively promote breast cancer cell malignancy. Interestingly, it was found that premalignant MCF10DCIS.com cells exposed to HA mineral adopted morphological changes associated with increased invasiveness and exhibited increased motility that was dependent on IL-8 signaling. Furthermore, DCIS xenograft tumors initiated in HA scaffolds exhibited evidence of increased malignant progression. Meanwhile, chapter 3 describes a multiscale characterization of the bone metastatic site in animal models of advanced breast cancer. Here, by combining high resolution X-ray scattering analysis with large area Raman imaging, backscattered electron microscopy, histopathology, and micro-computed tomography, it was observed that HA nanocrystal immaturity may be linked with secondary tumor formation in bone and that mammary tumors remotely alter HA nanostructure via possible osteogenic mechanisms. Collectively, the results from this work suggest a dynamic reciprocity between breast cancer cells and the HA embedded within their mineralized microenvironments. More studies will be needed to elucidate the mechanisms by which tumor cell-HA interactions drive malignancy to potentially identify improved therapeutic strategies. Importantly, this work has provided a framework for how future studies could utilize tissue engineering and materials science approaches to investigate mineralized tumor microenvironments relevant to breast cancer and bone metastasis.