Epithelial cells are the cells that turn cancerous, and in the normal mammary gland, epithelial cells are surrounded by a group of proteins known as the extracellular matrix (ECM). The composition and function of mammary ECM is under hormone/reproductive control, and ECM changes contribute to tumor outcomes in murine models. For example, during weaning-induced mammary gland involution, stiff and linear collagen fibers dominate the mammary ECM and contribute to tumor growth, invasion, and metastasis. In contrast, in the parous mammary gland, after the mammary gland has returned to its pre-pregnant resting state, mammary collagen fibers are mechanically soft and less linear. Further, this `parous' collagen has been shown to contribute to breast cancer suppression. We found a type I interferon gene signature that was dependent on collagen organization, and type I interferons are known to regulate dendritic cell (DC) function. DC cells are critical for the immune system to kill cancer cells, thus our preliminary data suggests that reproductive history, through the modulation of breast ECM, can determine whether a tumor is recognized by the immune system and eliminated. The objective of this proposal is to understand if mammary ECM, and particularly collagen organization, in the mammary gland of involution and parous states, alters dendritic cells in a manner which contributes to either tumor promotion or tumor suppression, respectively. Unique 3D in vitro models will be used to assess the effects of ECM on DC phenotype and function.
In Aim 1 a, ECM will be isolated from the mammary gland of involution or parous mice, and in Aim 1b, a reductionist 3D in vitro model of the stiff and soft collagen will be used to assess influence on DC phenotype and function. In addition to these in vitro approaches, assessment of in vivo mammary dendritic cells aims to understand if differences in reproductive state alter DC phenotype and function (Aim 2a). Lastly, in Aim 2b, the role of DCs in the tumor-promotional involution mammary gland and the tumor suppressed parous mammary gland will be tested by using a tumor model lacking DCs. This combined approach using both in vitro and in vivo models is expected to greatly contribute to understanding the impact of reproductive status on ECM-DC interactions. Furthermore, these studies extend to understanding the potential implications of ECM-DC interactions in the pathogenesis of cancer. Understanding ECM-DC interactions in cancer has the potential of elucidating a novel therapeutic node that could be targeted to enhance the efficacy of DC-based cancer immunotherapies, which have underperformed in the clinical setting, but are recognized for their high- impact potential in revolutionizing cancer therapy.
Early-age pregnancy associates with a transient period of enhanced tumor progression after weaning, following by a long period of tumor suppression, identifying reproductive windows of increased and decreased breast cancer risk, respectively. An unexplored mediator of these risk windows is interactions between the mammary extracellular matrix (ECM) and dendritic cell function, as mammary ECM function is hormonally regulated. The aim of this proposal is to understand if reproductively-altered ECM changes affect dendritic cell function as a means to dictate tumor outcome. These studies may identify a novel, and therapeutically targetable, aspect of reproductively-controlled mammary cancers.
| Betts, Courtney B; Pennock, Nathan D; Caruso, Breanna P et al. (2018) Mucosal Immunity in the Female Murine Mammary Gland. J Immunol 201:734-746 |
