Novel Cell-matrix Markers and Drivers of Breast Cancer

Institution: California Pacific Medical Center Research Institute
Investigator(s): John Muschler, Ph.D. -
Award Cycle: 2011 (Cycle 17) Grant #: 17IB-0045 Award: $262,500
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2011)

A critical determinant of breast cancer progression is the genesis of abnormal interactions between the cancer cells and their microenvironment. Influencial components of the normal and cancer microenvironment are extracellular matrix (ECM) molecules. Receptors for ECM molecules undergo changes in expression in breast cancers, and these alterations are associated with disease progression. Thus, novel therapies that target ECM receptors would have broad utility.

My laboratory has recently identified the presence of a novel ECM receptor on the surface of breast cancer cells, called Lutheran or BCAM. It appears to bind with high affinity to the laminin α5 subunit, a component of the ECM. The α5 laminins are virtually uniform elements of the breast tumor microenvironment; therefore, aberrant adhesive interactions between BCAM and α5 laminins can potentially drive breast cancer progression at multiple stages. Recently, we have established that elevated BCAM expression arises frequently in human breast cancers, including both invasive breast cancers and a subset of ductal carcinoma in situ (DCIS).

To further study the consequence of elevated BCAM expression on cell behavior, in this project we will manipulate BCAM expression in normal and cancerous breast epithelial cells and measure the resulting changes in cell function using both in cell-based and animal-model assays. The cell-based assays will employ 3D assays of growth, morphogenesis, and invasion within “gels” of reconstituted ECM/basement membrane proteins. Animal work will employ xenograft (mouse model) assays of human breast cancer growth and metastasis in the presence and absence of elevated BCAM expression. In addition, a genetically engineered mouse model is being generated to produce elevated BCAM expression in the normal mouse mammary epithelium, and will be analyzed for disruption of normal mammary tissue morphogenesis and homeostasis. Finally, we will determine whether BCAM can act as a biomarker of breast cancer progression.




Final Report (2014)

The interactions between cells and their microenvironment serve as essential regulators of tissue architecture and function, and changes in these interactions contribute to the progression of breast cancers. Although such changes are recognized as potentially useful biomarkers and therapeutic targets, they remain poorly defined. The goal of this work was to elucidate the changes at the cancer cell surface that modify cell interactions with the cell microenvironment and possibly drive cancer heterogeneity and cancer progression.

The present study has focused first on a cell-surface molecule called "BCAM", which is a known mediator of cell adhesion and expressed highly in some breast cancers, but has not been investigated in breast cancer progression. We have employed multiple approaches to test for BCAM functions in breast cells that include studies in cell culture and transgenic animals, staining of human tissue biopsies, and computer based interrogation of human gene expression data. Tests in cell culture and animal models have not yielded significant measures of BCAM functions. However, we have demonstrated a clear association between the production level of BCAM and breast cancer subtypes, with high BCAM levels in ER+ and Her2+ cancers, and low levels in triple negative cancers and in higher grade tumors. Results of these studies have compelled an expanded investigation into cell-microenvironment interactions, focusing on changes in the expression of extracellular matrix proteins called laminins (some of which bind BCAM). We have used transgenic mice to enact the genetic deletion of specific laminin subunits from the mammary gland, thereby modeling changes known to occur in the breast cancer microenvironment. Some of these mice have demonstrated mammary hyperplasia (excessive mammary epithelial outgrowth) with age, suggesting roles in epithelial growth suppression, and possibly tumor suppression. These in vivo results are complemented by computational methods that reveal a reduction in disease-free survival correlated with the lost of specific laminin subunit gene expression, and the loss of several associated genes that appear coordinately regulated with laminins.

Our results establish BCAM as a previously unrecognized factor in breast cancer heterogeneity and as a novel player in the dynamic cell adhesion interactions between breast cancer cells and their microenvironment. We also reveal in breast cancer progression a coordinated down-regulation of proteins associated with specific laminin subunits that we hypothesize to compromise an important tumor suppression mechanism. Our future objectives are aimed at further elucidating these changes in cell adhesion interactions that arise in breast cancers, revealing the stage and subtype specific alterations, and determining the functional consequence of these changes. The ultimate goal is to uncover new axes of cancer regulation that are amenable to therapeutic intervention.