Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway

SIMPLE SUMMARY: Studies from our group and others have established Kindlin-2 that is expressed in the cancer cells as a major driver of tumor progression and metastasis in breast cancer (BC). The role of Kindlin-2 that is expressed in the mammary glands (tumor microenvironment) in the pathogenesis of BC has, however, not been investigated. To this end, we generated a mouse strain that specifically lacks expression of Kindlin-2 in the basal cells within the mouse mammary glands. Loss of Kindlin-2 in this mammary gland compartment, while having no effect on mouse development, significantly inhibited BC tumors growth and metastasis when these Kindlin-2-deficient mice were challenged with mammary fat pad injection of cancer cells. At the molecular signaling level, we found that Kindlin-2 plays a significant role in regulating BC progression and metastasis in both the cancer cells and the tumor microenvironment (mammary epithelial cells) downstream of a TGF-β/EGF signaling axis. ABSTRACT: Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2(lox/lox)) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2(lox/lox) mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.