Letter to the Editor
Dear Editor,
I would like to briefly describe the regulatory functions of Rab GTPases on vesicular transport of cell surface-bound proteins and/or molecules in Breast cancer (BC) progression and metastases.
A Brief Overview of BC Progression and Metastases
BC, a heterogeneous disease, is thought to be the second leading cause of death in women globally. In only 70-80% of the BC patients with early-stage, non-metastatic disease is curable [1]. In advanced BC metastasis, it is incurable [2]. The major factors predominantly causing BC occurrence, in general, include [1] reproductive and hormonal risk factors such as early age and/or later age at menopause, advanced age at first birth, less breast feeding, menopausal hormone therapy, and oral contraceptives, lifestyle risk factors such as excess body weight, physical inactivity, and alcohol intake, as well as genetic predisposition (germline mutations of high-penetrance genes such as BC1/2 (BRCA1/2), partner and localizer of BRCA2 (PALB2), ATM, checkpoint kinase 2 (CHEK2), RAD51 homolog C (RAD51C), BRCA1 associated RING domain 1 (BARD1), TP53, etc.] [3-9], and notably the activation of human epidermal growth factor receptor 2 (HER2, encoded ERBB2) [10]. Many of such events are accelerated by vesicle-mediated transport of cargos among subcellular compartments. Of these, Rab GTPases, mediating via coordinated and dynamic intracellular membrane trafficking alongside cytoskeletal pathways, determine the homeostatic maintenance and a variety of cellular functions in many types of human cells such as neuron cells [11,12], immune cells [13-15], osteoclasts [16-21], cancer cells [22-24], and bone metastasis [25,26], etc. A recent study has revealed that Rab26 negatively regulates migration and invasion of BC cells via abrogating the focal adhesion association of Src kinase and inducing endosomal translocation of Src [23] whereas Rab25, also known as Rab11c, alleviated apoptosis and enhanced the aggressiveness of BC cells [27]. Besides, Rab11 is thought to be essential for regulating the localization of Arf6 in MDA-MB-231 BC cells, thereby modulating the cell motility [27]. Rab27B, an oncoprotein, controlled vesicular exocytosis and released vital growth regulators into the tumor microenvironment, leading to promote the invasiveness and metastasis in ER-positive human BC tumors [28]. However, whether Rab GTPases work individually or in a related network is still controversial. Furthermore, more studies need to be done to investigate functional roles of other Rab GTPases in cancers to hopefully establish the program of drug development that targets Rab GTPases. In conclusion, it might be a potential strategy to potentiate BC cancer treatment methods.
References
2. Riggio AI, Varley KE, Welm AL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer. 2021 Jan;124(1):13-26.
3. Marvalim C, Datta A, Lee SC. Role of p53 in breast cancer progression: An insight into p53 targeted therapy. Theranostics. 2023 Feb 27;13(4):1421-42.
4. Moslemi M, Moradi Y, Dehghanbanadaki H, Afkhami H, Khaledi M, Sedighimehr N, et al. The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis. BMC Cancer. 2021 Jan 5;21(1):27.
5. Nickoloff JA, Jaiswal AS, Sharma N, Williamson EA, Tran MT, Arris D, et al. Cellular Responses to Widespread DNA Replication Stress. Int J Mol Sci. 2023 Nov 29;24(23):16903.
6. Rainville I, Hatcher S, Rosenthal E, Larson K, Bernhisel R, Meek S, et al. High risk of breast cancer in women with biallelic pathogenic variants in CHEK2. Breast Cancer Res Treat. 2020 Apr;180(2):503-9.
7. Sadeghi F, Asgari M, Matloubi M, Ranjbar M, Karkhaneh Yousefi N, Azari T, et al. Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays. Biol Proced Online. 2020 Oct 1;22:23.
8. Wu J, Aini A, Ma B. Mutations in exon region of BRCA1-related RING domain 1 gene and risk of breast cancer. Mol Genet Genomic Med. 2022 Mar;10(3):e1847.
9. Wu R, Patel A, Tokumaru Y, Asaoka M, Oshi M, Yan L, et al. High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer. Breast Cancer Res Treat. 2022 May;193(1):49-63.
10. Riecke K, Witzel I. Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2. Breast Care (Basel). 2020 Dec;15(6):579-85.
11. Nik Akhtar S, Bunner WP, Brennan E, Lu Q, Szatmari EM. Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders. Front Cell Neurosci. 2023 Jan 27;17:1084769.
12. Li Y, Wang X, Xie JX, Song N. [Research progress of Rab proteins in neurodegenerative diseases]. Sheng Li Xue Bao. 2021 Apr 25;73(2):315-28.
13. Jiang X, Yang L, Gao Q, Liu Y, Feng X, Ye S, et al. The Role of RAB GTPases and Its Potential in Predicting Immunotherapy Response and Prognosis in Colorectal Cancer. Front Genet. 2022 Jan 28;13:828373.
14. Runsala M, Kuokkanen E, Uski E, Šuštar V, Balci MÖ, Rajala J, Paavola V, Mattila PK. The Small GTPase Rab7 Regulates Antigen Processing in B Cells in a Possible Interplay with Autophagy Machinery. Cells. 2023 Nov 2;12(21):2566.
15. Tokuhisa M, Kadowaki T, Ogawa K, Yamaguchi Y, Kido MA, Gao W, et al. Expression and localisation of Rab44 in immune-related cells change during cell differentiation and stimulation. Sci Rep. 2020 Jul 1;10(1):10728.
16. Feng Y, Tran MT, Lu Y, Htike K, Okusha Y, Sogawa C, et al. Rab34 plays a critical role as a bidirectional regulator of osteoclastogenesis. Cell Biochem Funct. 2022 Apr;40(3):263-77.
17. Noda K, Lu SL, Chen S, Tokuda K, Li Y, Hao F, et al. Characterization of Rab32- and Rab38-positive lysosome-related organelles in osteoclasts and macrophages. J Biol Chem. 2023 Oct;299(10):105191.
18. Okusha Y, Tran MT, Itagaki M, Sogawa C, Eguchi T, Okui T, et al. Rab11A Functions as a Negative Regulator of Osteoclastogenesis through Dictating Lysosome-Induced Proteolysis of c-fms and RANK Surface Receptors. Cells. 2020 Oct 31;9(11):2384.
19. Tran MT, Okusha Y, Feng Y, Morimatsu M, Wei P, Sogawa C, et al. The Inhibitory Role of Rab11b in Osteoclastogenesis through Triggering Lysosome-Induced Degradation of c-Fms and RANK Surface Receptors. Int J Mol Sci. 2020 Dec 8;21(24):9352.
20. Tran MT, Okusha Y, Feng Y, Sogawa C, Eguchi T, Kadowaki T, et al. A novel role of HSP90 in regulating osteoclastogenesis by abrogating Rab11b-driven transport. Biochim Biophys Acta Mol Cell Res. 2021 Sep;1868(10):119096.
21. Tran MT, Okusha Y, Htike K, Sogawa C, Eguchi T, Kadowaki T, et al. HSP90 drives the Rab11a-mediated vesicular transport of the cell surface receptors in osteoclasts. Cell Biochem Funct. 2022 Dec;40(8):838-55.
22. Choi J, Sung JY, Lee S, Yoo J, Rongo C, Kim YN, et al. Rab8 and Rabin8-Mediated Tumor Formation by Hyperactivated EGFR Signaling via FGFR Signaling. Int J Mol Sci. 2020 Oct 20;21(20):7770.
23. Liu H, Zhou Y, Qiu H, Zhuang R, Han Y, Liu X, et al. Rab26 suppresses migration and invasion of breast cancer cells through mediating autophagic degradation of phosphorylated Src. Cell Death Dis. 2021 Mar 17;12(4):284.
24. Yoshida K, Htike K, Eguchi T, Kawai H, Eain HS, Tran MT, et al. Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. J Oral Biosci. 2024 Mar;66(1):205-16.
25. Tran MT. Metastatic breast cancer-derived exosomes and osteoclast-mediated bone metastasis. J Breast Cancer Res. 2023;3(1):8-10.
26. Tran MT. Overview of Ca2+ signaling in lung cancer progression and metastatic lung cancer with bone metastasis. Explor Target Antitumor Ther. 2021;2(3):249-265.
27. Ferro E, Bosia C, Campa CC. RAB11-Mediated Trafficking and Human Cancers: An Updated Review. Biology (Basel). 2021 Jan 4;10(1):26.
28. Zavala-Barrera C, Del-Río-Robles JE, García-Jiménez I, Egusquiza-Alvarez CA, Hernández-Maldonado JP, Vázquez-Prado J, et al. The calcium sensing receptor (CaSR) promotes Rab27B expression and activity to control secretion in breast cancer cells. Biochim Biophys Acta Mol Cell Res. 2021 Jun;1868(7):119026.