The Potential Role of Profilin in Metastatic Breast Cancer

INTRODUCTION Breast cancer is the most common form of cancer among women. In fact, 1 in 8 women are to be diagnosed with invasive breast cancer, the fatal form of breast cancer. Already in 2016, there have been approximately 250,000 cases of metastatic breast cancer with a death total of around 41,000 women [1]. Clearly, there is a need for better treatment options or detection methods for this form of cancer. The actual deaths, however, are not caused by the breast cancer itself. Rather, it is the spread, or metastasis, of cancer niches from the primary site in the breast to secondary sites such as lung or lymphatic tissue that leads to death [2]. Metastasis is characterized by significant cell migration. Such migration is regulated by the dynamic actin cytoskeleton. Actin, in turn, is regulated by a protein known as profilin (Pfn) which, under normal physiological conditions, helps to sequester free actin monomers and attach them to further actin polymerization [3]. In pathophysiological states, lower levels of profilin have been associated with more aggressive and metastatic breast cancer [4]. However, Pfn, which comes in two isomers: profilin-1 (Pfn1) and profilin-2 (Pfn-2), regulates cancer differently depending on the stage that the disease is in. Our lab has shown that in early stages of cancer, profilin induces the migration of cancer cells to secondary locations; however, once these cells reach the new sites profilin actually impedes the recolonization of a new niche [2]. Clearly, Pfn’s function in cancer is not as cut and dry as other proteins such as Ras or p53. Moreover, E-cadherin is a transmembrane cell-cell connecting protein which has been shown to be a tumor suppressor. Loss of E-cadherin induces what is known as epithelial to mesenchymal transition (EMT) in which cells become unbound from each other and are thus allowed to migrate [4]. EMT is a hallmark of metastatic cancers. Structurally, E-cadherin is anchored to the cell via adaptor proteins that are then attached to actin fibers [5]. Our lab has previously shown that this structural relationship also plays a role with the signaling axis of both profilin and E-cadherin. When Pfn-1 is knocked down via siRNA in MDA-MB-231 breast cancer cells, there is a knockdown of 46% cell-cell connections made through E-cadherin [4].