Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating α6- and β1-integrin-dependent adhesion. Conversely, the overexpression of FER in non-metastatic breast cancer cells induces pro-invasive features. FER drives anoikis resistance, regulates tumour growth and is necessary for metastasis in a mouse model of human breast cancer. In human invasive breast cancer, high FER expression is an independent prognostic factor that correlates with high-grade basal/triple-negative tumours and worse overall survival, especially in lymph node-negative patients. These findings establish FER as a promising target for the prevention and inhibition of metastatic breast cancer.
Kaiso is a BTB/POZ transcription factor that is ubiquitously expressed in multiple cell types and functions as a transcriptional repressor and activator. Little is known about Kaiso expression and localization in breast cancer. Here, we have related pathological features and molecular subtypes to Kaiso expression in 477 cases of human invasive breast cancer. Nuclear Kaiso was predominantly found in invasive ductal carcinoma (IDC) (p = 0.007), while cytoplasmic Kaiso expression was linked to invasive lobular carcinoma (ILC) (p = 0.006). Although cytoplasmic Kaiso did not correlate to clinicopathological features, we found a significant correlation between nuclear Kaiso, high histological grade (p = 0.023), ERα negativity (p = 0.001), and the HER2-driven and basal/triple-negative breast cancers (p = 0.018). Interestingly, nuclear Kaiso was also abundant in BRCA1-associated breast cancer (p<0.001) and invasive breast cancer overexpressing EGFR (p = 0.019). We observed a correlation between nuclear Kaiso and membrane-localized E-cadherin and p120-catenin (p120) (p<0.01). In contrast, cytoplasmic p120 strongly correlated with loss of E-cadherin and low nuclear Kaiso (p = 0.005). We could confirm these findings in human ILC cells and cell lines derived from conditional mouse models of ILC. Moreover, we present functional data that substantiate a mechanism whereby E-cadherin controls p120-mediated relief of Kaiso-dependent gene repression. In conclusion, our data indicate that nuclear Kaiso is common in clinically aggressive ductal breast cancer, while cytoplasmic Kaiso and a p120-mediated relief of Kaiso-dependent transcriptional repression characterize ILC.
The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often found deregulated in breast cancer. Here we provide an overview on the functional and molecular identification of mammary stem cells in the context of both normal breast development and breast cancer. We discuss the contribution of some key signaling pathways with an emphasis on Notch receptor signaling, a cell fate determination pathway often deregulated in breast cancer. A further understanding of the biological roles of the Notch pathway in mammary stem cell behavior and carcinogenesis might be relevant for the development of future therapies.
MRP1 (ABCC1) is known to be localized in lipid rafts. Here we show in two different cell lines that localization of Mrp1/MRP1 (Abcc1/ABCC1) in lipid rafts and its function as an efflux pump are dependent on cortical actin. Latrunculin B disrupts both cortical actin and actin stress fibers. This results in partial loss of actin and Mrp1/MRP1 (Abcc1/ABCC1) from detergent-free lipid raft fractions, partial internalization of Mrp1/MRP1 (Abcc1/ ABCC1), and reduction of Mrp1/MRP1 (Abcc1/ABCC1)-mediated efflux. Pretreatment with nocodazole prevents latrunculin B-induced loss of cortical actin and all effects of latrunculin B on Mrp1 (Abcc1) localization and activity. However, pretreatment with tyrphostin A23 does not prevent latrunculin B-induced loss of cortical actin, lipid raft association, and efflux activity, but it does prevent latrunculin B-induced internalization of Mrp1 (Abcc1). Cytochalasin D disrupts actin stress fibers but not cortical actin and this inhibitor much less affects Mrp1/ MRP1 (Abcc1/ABCC1) localization in lipid rafts, internalization, and efflux activity. In conclusion, cortical actin disruption results in reduced Mrp1/MRP1 (Abcc1/ABCC1) activity concomitant with a partial shift of Mrp1/MRP1 (Abcc1/ABCC1) out of lipid raft fractions and partial internalization of the ABC transporter. The results suggest that reduced Mrp1 (Abcc1) function is correlated to the loss of lipid raft association but not internalization of Mrp1 (Abcc1).
Lobular carcinoma is a breast cancer subtype comprising approximately 15 % of all breast cancer cases. Clinical diagnosis of this subtype is difficult due to a characteristic growth pattern that inhibits detection using palpation or standard X-ray mammography. While clinical intervention based on hormone antagonists has proven an effective strategy, hormone receptor negative or nonresponsive disease cannot be treated successfully, indicating the need for alternative curative approaches. In contrast to its well-defined histopathological characteristics that were first recognized a century ago, the surface of the underlying biology has only recently been scratched. Progress was made in understanding the biology of the disease, which will hopefully have its impact on future treatment modalities and initiate development of novel intervention strategies. Here, we review the pathological and molecular features of lobular breast cancer and report on the currently known mechanisms that control disease development and progression. Finally we will reflect on past, present, and future treatment options.
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