cancers Review Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis Patricia Fernández-Nogueira 1,2, *, Gemma Fuster 1,3,4 , Álvaro Gutierrez-Uzquiza 5,6 , Pere Gascón 1 , Neus Carbó 1 and Paloma Bragado 5,6, *   Citation: Fernández-Nogueira, P.; Fuster, G.; Gutierrez-Uzquiza, Á.; Gascón, P.; Carbó, N.; Bragado, P. Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis. Cancers 2021, 13, 3146. https://doi.org/10.3390/cancers 13133146 Academic Editors: Stephan Joel Reshkin and Rosa Angela Cardone Received: 30 April 2021 Accepted: 16 June 2021 Published: 23 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), 08028 Barcelona, Spain; gemmafuster@ub.edu (G.F.); peregascon@ub.edu (P.G.); ncarbo@ub.edu (N.C.) 2 Department of Biomedicine, School of Medicine, University of Barcelona, 08028 Barcelona, Spain 3 Department of Biochemistry & Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain 4 Department of Biosciences, Faculty of Sciences and Technology, University of Vic, 08500 Vic, Spain 5 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain; alguuz@ucm.es 6 Health Research Institute of the Hospital Clínico San Carlos, 28040 Madrid, Spain * Correspondence: pfernandezn@ub.edu (P.F.-N.);pbragado@ucm.es (P.B.); Tel.: +34-934021871 (P.F.-N.); +34-913941853 (P.B.) Simple Summary: Breast cancer is a major public health problem with a large impact on the life of patients and their families. It is a highly curable disease when detected early, and an inevitably mortal disease when discovered too late. Therapy resistance and metastases are the most critical clinical issues faced by breast cancer oncologists nowadays. It has become evident that interactions between carcinoma cells and tumor microenvironment are an essential part of tumor growth and pro- gression. Cells that support the function of epithelial cells, like cancer-associated fibroblasts (CAFs), contribute to therapy resistance and metastasis via the production of several secreted factors and direct interaction with cancer cells. Here we review the role of CAFs in radiotherapy, chemotherapy, endocrine and targeted therapies resistance. We also highlight the role of CAFs and fibroblasts from metastatic sites in metastasis progression. Finally, we discuss advances and potential therapeutic strategies to target CAFs for overcoming resistance and preventing metastases. Abstract: Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management. Keywords: breast cancer; cancer-associated fibroblasts; therapy resistance; metastasis 1. Introduction Breast cancer (BrCa) is the most commonly diagnosed cancer among females and the first leading cause of cancer death in women [1]. Despite the fact that the advancements in Cancers 2021, 13, 3146. https://doi.org/10.3390/cancers13133146 https://www.mdpi.com/journal/cancers