Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

cancers Review Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae Matthew G. K. Benesch 1,2 , Xiaoyun Tang 2 and David N. Brindley 2, * 1 2 * Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL AlB 3V6, Canada; Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada; Correspondence: ; Tel.: +1-780-492-2078 Received: 7 January 2020; Accepted: 1 February 2020; Published: 6 February 2020



 Abstract: After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers. Keywords: lysophosphatidic acid; lipid phosphate phosphatases; GLPG1690; chemoresistance; radiotherapy; metastasis; tumor microenvironment 1. Introduction—History of Breast Cancer, Current Management, and Remaining Challenges Breast cancer is believed to be the oldest documented cancer, described in an Egyptian scroll dating to 1700 BCE as a bulging mass for which no cure was possible [1]. Writings of Hippocrates and Galen describe crab-like lesions (karkinoma) of the breast with swollen blood vessels and a hardened, matted surface, from which we get the word, “carcinoma” [2]. These works also describe a “black bile” discharge from breasts, which we now recognize as signs of symptomatic breast cancer [3,4]. Virtually no progress in treatment was made until the first mastectomies were performed in the 1750s. Once the concepts of lymphatic spread and metastasis were understood, the radical mastectomies of the early 20th century gave way to lumpectomies and sentinel lymph node biopsies. The 20th century saw cancer treatment develop into a trimodal entity—surgery, the “cold knife”, the remove the cancer with a margin of healthy tissue; radiotherapy, “the hot knife”, to eradicate any remaining cells within the surgical field; and chemotherapy, to both eliminate any circulating cancer cells and prevent local reoccurrence. Clinically, the treatment of breast cancer has made incredible progress, but challenges remain. Examining SEER (Surveillance, Epidemiology and End Results) data from the United States, among the largest cancer epidemiology repositories in the world, overall 5-year survival has risen from 74.6% to 92.4% from 1975 to 2015 [5]. However, the gains made in survival do not equally apply to all groups of breast cancer at disease presentation. Survival for regional breast cancer has increased from 52% to 85%, whereas survival from distant or metastatic disease has only marginally improved from 13% to Cancers 2020, 12, 374; doi:10.3390/cancers12020374 www.mdpi.com/journal/cancers Cancers 2020, 12, 374 2 of 18 about 20% in 30 years [5,6]. Because treatment of metastatic disease rests largely on chemotherapeutic interventions, discovering how to overcome either inherent or acquired chemoresistance mechanisms is necessary to both prolong remission and increase survival rates. Chemotherapeutic interventions for breast cancer depend primarily on the estrogen and progesterone hormonal status of the tumors. Whether localized or disseminated, the treatment of choice is based on endocrine therapies, including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and selective estrogen receptor down-regulators (SERDs) [7]. A third receptor, HER2/neu (human epidermal growth factor receptor 2), is overexpressed in up to 20% of breast cancers and it is targeted with receptor blockers including trastuzumab, pertuzumab, neratinib, and lapatinib [8]. Breast cancers that express none of these receptors are labeled triple negative, accounting for 10%–20% of all cases, and typically they are poorly differentiated with higher proliferation rates compared to hormone receptor-positive cancers. Their treatment depends on cytotoxic taxane-, anthracycline-, and platinum-based regimens that target cell-cycle progression. In approximately 20% of these patients, tumors will completely regress after such therapy (complete pathological response), but for those patients that do not achieve this level of response, the risk of reoccurrence and death from metastases are many fold more than for those with hormone-positive cancers [9,10]. Overall, 90% of breast cancer patients who develop metastatic disease become resistant to their chemotherapy regimens [11]. Despite the high heterogeneity and a plethora of molecular signatures, there are common mechanisms of chemotherapy resistance in triple-negative breast cancers, which have also become recognized in recent years to be associated with treatment failure against hormonal and HER2/neu targeted treatments [10,12]. By no means exhaustive, three of these mechanisms of interest in breast cancer research are ATP-binding cassette (ABC) transporters, cancer stem cells, and microRNAs. Briefly, ABC transporters, or multi-drug resistance transporters, use ATP to export a host of chemotherapeutic agents from cancer cells. Of the 49 known transporters in humans, three are most often implicated in cancer therapy resistance: multidrug resistance protein 1 (MDR1 or ABCB1), multidrug resistance-associated protein 1 (MRP1 or ABCC1), and breast cancer resistance protein (BCRP or ABCG2) [13]. Next, cancer stem cells are a pluripotent sub-population of cells that are intrinsically resistant to chemotherapy due to their quiescence and dormancy. While cancer cells within a tumor are killed by treatment, these highly plastic survivors spawn cells with genetic adaptations permitting resistance to subsequent rounds of treatment [14]. Normally comprising 1% of the total tumor cell population, their fraction increases up to 30% with tumor progression following treatment failure [15]. MicroRNAs are a family of small non-coding single-stranded regulatory RNAs that bind to the 30 -untranslated region of target messenger RNAs to act as post-transcription downregulators of translation [16]. Cancer cells manipulate (...truncated)