cancers Review Ca2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer Dongun Lee and Jeong Hee Hong * Department of Health Sciences and Technology, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-32-899-6682 Simple Summary: Intracellular Ca2+ signaling is a critical factor in breast cancer metastasis. In the pro- liferation stage, increases in intracellular Ca2+ concentration through voltage-dependent Ca2+ chan- 2+ nels, P2Y2 channels, transient receptor potential (TRP) channels, store-operated Ca channels 2+ (SOCCs), and IP3 receptors and a decrease in intracellular Ca concentration through plasma membrane Ca2+ ATPases and secretory pathway Ca2+ ATPases (SPCA) activate breast cancer cell proliferation. TRPM7, SOCC, inositol trisphosphate receptor (IP3R), ryanodine receptor (RyR), and sarco-/endo-plasmic reticulum Ca2+-ATPase (SERCA) increase the expression of epithelial-to- mesenchymal transition (EMT)-related proteins; meanwhile, SPCA and the Na+/Ca2+ exchanger (NCX) control the activation of EMT-related proteins. Increased Ca2+ through TRPC1, TRPM7/8, P2X7, and SOCC enhances breast cancer cell migration. The stromal interaction molecule (STIM)-Orai 2+ complex, P2X7, and Ca sensing receptors are involved in invadopodia. Various pharmacological agents for Ca2+ channels have been proposed against breast cancer and have provided potential strategies for treating metastatic processes. Abstract: Metastatic features of breast cancer in the brain are considered a common pathology in fe- Citation: Lee, D.; Hong, J.H. Ca2+ male patients with late-stage breast cancer. Ca2+ signaling and the overexpression pattern of Ca2+ Signaling as the Untact Mode during channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor Signaling in Metastatic Breast Cancer. development can be mediated by inhibiting Ca2+ channels. Although the therapeutic potential of Cancers 2021, 13, 1473. https:// inhibiting Ca2+ channels against breast cancer has been demonstrated, the relationship between doi.org/10.3390/cancers13061473 breast cancer metastasis and Ca2+ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca2+-related proteins and chan- Academic Editors: Juan A. Rosado 2+ and Tarik Smani nels during the stages of metastatic breast cancer by evaluating Ca signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca2+ channels with Ca2+ Received: 15 February 2021 channel inhibitors and combined applications will advance treatment strategies for breast cancer Accepted: 22 March 2021 metastasis to the brain. Published: 23 March 2021 Keywords: Ca2+ channels; breast cancer; Ca2+ signaling; brain metastasis Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Cancer metastasis occurs in several stages, including proliferation, epithelial-to- mesenchymal transition (EMT), invasion, transport, colonization, and angiogenesis (Figure1)[1] . In fully developed tumorigenesis stages, circulating tumor cells move into Copyright: © 2021 by the authors. another tissue and transform into mesenchymal stem cell-like cells as a result of EMT [2,3]. Licensee MDPI, Basel, Switzerland. EMT is the initiation step in cancer metastasis [4]. Tumor cells are transported through This article is an open access article the bloodstream after invading blood vessels [5–7] in a process called intravasation [8]. distributed under the terms and The metastasized tumor cells attach and grow via colonization; then, the blood vessels that conditions of the Creative Commons supply nutrients are generated during angiogenesis, leading to cancer development [2,9,10]. Attribution (CC BY) license (https:// In many stages of metastasis, the proteins and factors related to metastasis are intricate [11]. creativecommons.org/licenses/by/ Therefore, messenger signaling to block metastasis and tumorigenesis is necessary for 4.0/). Cancers 2021, 13, 1473. https://doi.org/10.3390/cancers13061473 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 19 Cancers 2021, 13, 1473 2 of 18 intricate [11]. Therefore, messenger signaling to block metastasis and tumorigenesis is thenecessary fundamental for the processes fundamental that regulateprocesses initial that signalingregulate initial factors, signaling but protein factors, signaling but protein is not. Breastsignaling cancer is not. is the Breast most cancer common is the cancer most type,common and cancer it has been type, considered and it has been one of considered the most malignantone of the cancersmost malignant in women cancers worldwide in women [12,13 worldwide]. Breast cancer [12,13]. subtypes Breast cancer include subtypes triple- negativeinclude triple-negative and triple-positive andbreast triple-positive cancer resulting breast cancer from the resulting existence from and the nonexistence existence and of estrogennonexistence receptors, of estrogen progesterone receptors, receptors, progeste orrone human receptors, epidermal or human growth epidermal factor receptor-2 growth (HER2)factor receptor-2 [14,15]. Each (HER2) subtype [14,15]. has Each the following subtype has cell the lines: following triple-negative cell lines: (MDA-MB-231, triple-negative MDA-MB-486,(MDA-MB-231, and MDA-MB-486, MCF-10A [16 and,17 ]),MCF-10A triple-positive [16,17]), (BSMZ, triple-positive BT474, and (BSMZ, EFM192A BT474, [16 and]), andEFM192A hormone [16]), receptor-positive and hormone cellreceptor-positive lines that express cell estrogenlines that receptors express estrogen and progesterone receptors receptorsand progesterone in the absence receptors of HER2 in the (MCF-7absence andof HER2 T47D (MCF-7 [16]). Genotypic and T47D or[16]). phenotypic Genotypic het- or erogeneityphenotypic of heterogeneity breast cancer of is breast diverse. cancer While is triple-negativediverse. While triple-negative breast cancer generally breast cancer has thegenerally most aggressive has the most behavior aggressive and behavior poor clinical and poor outcomes clinical [18 outcomes–20], triple-positive [18–20], triple-pos- breast canceritive breast has alsocancer been has found also been to exhibit found to aggressive exhibit aggressive behavior, behavior, despite the despite availability the availa- of antibody-targetedbility of antibody-targeted therapy or therapy chemotherapy or chemotherapy [21]. [21]. FigureFigure 1.1.The The metastaticmetastatic pathwaypathway ofof breastbreast cancercancer cells.cells. ProliferatedProliferated breastbreast cancercancer cellscells areare trans-trans- formedformed into into mesenchymal-like mesenchymal-like cells cells and and undergo undergo invasion invasion and and intravasation intravasation to to bloodblood vessels.vessels. Trans-Trans- portingporting tumor tumor cells cells perform perform extravasation extravasation from from blood blood vessels vessels and and generate generate a cancerous a cancerous environment environ- ment through colonization and angiogenesis. through colonization and angiogenesis. InIn this this review, review, we we elucidate elucidate the the essential essential processes processes of metastasis of metastasis in breast in breast cancer. cancer. In par- In ticular,particular, Ca2+ Casignaling2+ signaling molecules molecules are are introduced, introduced, and and the the processes processes involved involved in in the thefun- fun- damentaldamental modulationmodulation ofof CaCa2+2+ signalingsignaling modulesmodules andand potentialpotential strategiesstrategies againstagainstbreast breast cancercancer are are addressed. addressed. 1.1.1.1. CaCa2+2+ Signaling-Associated Molecules TheThe physiologicalphysiological rolerole of of Ca Ca2+2+ signalingsignaling isis commonlycommonly knownknown toto includeinclude musclemuscle con-con- tractiontraction toto crosslinkcrosslink actin, myosin, myosin, and and muscle muscle fibers fibers [22]. [22 ].In Inaddition, addition, Ca Ca2+ signaling2+ signaling reg- regulatesulates physiological physiological and and pathological pathological cellular cellular pathways, pathways, including including cell cellproliferation, proliferation, dif- differentiation,ferentiation, migration, migration, muscle muscle contraction, contraction, neurotransmitter neurotransmitter release, release, and and fluid fluid secretion secre- 2+ tion[23–25]. [23– 25The]. regulation The regulation of cellular of cellular Ca2+ as Ca a keyas asignaling key signaling messenger messenger is precisely is precisely modu- 2+ modulatedlated by numerous by numerous Ca2+ channels Ca channels and transporters and transporters associated associated with the with membrane the membrane of intra- ofcellular intracellular compartments compartments or plasma or plasmamembranes membranes [26]. The [26 concentration]. The concentration of intracellular of intracel- Ca2+ 2+ 2+ lular([Ca2+ Ca]i) in ([Cathe resting]i) in state the restingis sustained state up is sustainedto 100 nM, up allowing to 100 nM,the use allowing of evoked the Ca use2+ offor 2+ evokedthe signaling Ca forpathways the signaling involved pathways in cellular involved functions in [26]. cellular Generally, functions evoked [26]. intracellular Generally, 2+ evokedCa2+ passes intracellular through Cathe endoplasmicpasses