<em>AKT1</em> and <em>CTNNB1</em> mutations as drivers of paclitaxel resistance in breast cancer cells

Altiparmak-Ulbegi,Gulsum; Hasbal-Celikok,Gozde; Aksoy-Sagirli,Pinar

doi:10.3892/ol.2025.15070

July-2025 Volume 30 Issue 1

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July-2025 Volume 30 Issue 1

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Article

AKT1 and CTNNB1 mutations as drivers of paclitaxel resistance in breast cancer cells

Authors:
- Gulsum Altiparmak-Ulbegi
- Gozde Hasbal-Celikok
- Pinar Aksoy-Sagirli
View Affiliations / Copyright

Affiliations: Department of Biochemistry, Faculty of Pharmacy, Istanbul University, 34116 Istanbul, Türkiye
Article Number: 324
|
Published online on: May 2, 2025

https://doi.org/10.3892/ol.2025.15070
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Abstract

Breast cancer (BC) is the most prevalent cancer type in the world, with increasing incidence rates. Drug resistance is a notable factor that limits the effectiveness of BC therapy. Paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane class, is commonly used in BC; however, its efficacy is often compromised by drug resistance, which is primarily attributed to genetic alterations. The phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) and wingless‑type MMTV integration site family/β‑catenin signaling pathways are involved in essential cellular processes, such as proliferation, apoptosis and maintenance of homeostasis. Dysregulated activation of these pathways is strongly associated with carcinogenesis and drug resistance. In the present study, the potential effects of AKT1 (E17K/E49K/L52R) and catenin β‑1 (CTNNB1; S33P/T41A/S45F) mutations on PTX resistance in BC were investigated in vitro using site‑directed mutagenesis, transient transfection, MTS assay and western blot analyses. The results of the present study indicated that AKT1‑E17K/E49K and CTNNB1‑S45F/T41A mutations induced PTX resistance compared with AKT1‑wild‑type (WT) and CTNNB1‑WT in MCF‑7 cells, respectively. In MDA‑MB‑231 cells, all three AKT1 mutations (E17K/E49K/L52R) triggered PTX resistance compared with AKT1‑WT, while none of the CTNNB1 mutations exhibited such an effect. In conclusion, AKT1 mutations may serve as a biomarker for PTX resistance in both estrogen receptor (ER)(+)/progesterone receptor (PR)(+)/HER2(‑) and triple negative BC, while CTNNB1 mutations may be a potential biomarker for PTX resistance in ER(+)/PR(+)/HER2(‑) BC.

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1	Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024. View Article : Google Scholar : PubMed/NCBI
2	Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, Vignat J, Gralow JR, Cardoso F, Siesling S and Soerjomataram I: Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 66:15–23. 2022. View Article : Google Scholar : PubMed/NCBI
3	Turashvili G and Brogi E: Tumor heterogeneity in breast cancer. Front Med (Lausanne). 4:2272017. View Article : Google Scholar : PubMed/NCBI
4	Tang Y, Wang Y, Kiani MF and Wang B: Classification, treatment strategy, and associated drug resistance in breast cancer. Clin Breast Cancer. 16:335–343. 2016. View Article : Google Scholar : PubMed/NCBI
5	Shi X, Wang J, Lei Y, Cong C, Tan D and Zhou X: Research progress on the PI3K/AKT signaling pathway in gynecological cancer. Mol Med Rep. 19:4529–4535. 2019.PubMed/NCBI
6	Noorolyai S, Shajari N, Baghbani E, Sadreddini S and Baradaran B: The relation between PI3K/AKT signaling pathway and cancer. Gene. 698:120–128. 2019. View Article : Google Scholar : PubMed/NCBI
7	Dong C, Wu J, Chen Y, Nie J and Chen C: Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer. Front Pharmacol. 12:6286902021. View Article : Google Scholar : PubMed/NCBI
8	Cidado J and Park BH: Targeting the PI3K/Akt/mTOR pathway for breast cancer therapy. J Mammary Gland Biol Neoplasia. 17:205–216. 2012. View Article : Google Scholar : PubMed/NCBI
9	Nicholson KM and Anderson NG: The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal. 14:381–395. 2002. View Article : Google Scholar : PubMed/NCBI
10	Basu A and Lambring CB: Akt isoforms: A family affair in breast cancer. Cancers. 13:34452021. View Article : Google Scholar : PubMed/NCBI
11	Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Bpguslawski S, Moses TY, Savage S, et al: A transforming mutation in the plekstrin homology domain of AKT1 in cancer. Nature. 448:439–444. 2007. View Article : Google Scholar : PubMed/NCBI
12	Askham JM, Platt F, Chambers PA, Snowden H, Taylor CF and Knowles MA: AKT1 mutations in bladder cancer: Identification of a novel oncogenic mutation that can co-operate with E17K. Oncogene. 29:150–155. 2010. View Article : Google Scholar : PubMed/NCBI
13	Parikh C, Janakiraman V, Wu WI, Foo CK, Kljavin NM, Chaudhuri S, Stawiski E, Lee B, Lin J, Li H, et al: Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers. Proc Natl Acad Sci USA. 109:19368–19373. 2012. View Article : Google Scholar : PubMed/NCBI
14	Hinz N and Jücker M: Distinct functions of AKT isoforms in breast cancer: A comprehensive review. Cell Commun Signal. 17:1–29. 2019. View Article : Google Scholar : PubMed/NCBI
15	Jung SH, Kim MS, Lee SH, Park HC, Choi HJ, Maeng L, Min KO, Kim J, Park TI, Shin OR, et al: Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung. Proc Natl Acad Sci USA. 113:10672–10677. 2016. View Article : Google Scholar : PubMed/NCBI
16	MacDonald BT, Tamai K and He X: Wnt/β-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI
17	Xu X, Zhang M, Xu F and Jiang S: Wnt signaling in breast cancer: Biological mechanisms, challenges and opportunities. Mol Cancer. 19:1652020. View Article : Google Scholar : PubMed/NCBI
18	Clevers H: Wnt/β-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
19	Kimelman D and Xu W: β-Catenin destruction complex: Insights and questions from a structural perspective. Oncogene. 25:7482–7491. 2006. View Article : Google Scholar : PubMed/NCBI
20	Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G and Yin G: Wnt/β-catenin signaling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduc Target Ther. 7:32022. View Article : Google Scholar
21	Gao C, Wang Y, Broaddus R, Sun L, Xue F and Zhang W: Exon 3 mutations of CTNNB1 drive tumorigenesis: A review. Oncotarget. 9:5492–5508. 2018. View Article : Google Scholar : PubMed/NCBI
22	Van Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES and Buendia MA: Nuclear accumulation of mutated β-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 155:703–710. 1999. View Article : Google Scholar
23	Tanaka Y, Kato K, Notohara K, Hojo H, Ijiri R, Miyake T, Nagahara N, Sasaki F, Kitagawa N, Nakatani Y and Kobayashi Y: Frequent β-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudo papillary neoplasm. Cancer Res. 61:8401–8404. 2001.PubMed/NCBI
24	Machin P, Catasus L, Pons C, Muñoz J, Matias-Guiu X and Prat J: CTNNB1 mutations and β-catenin expression in endometrial carcinomas. Hum Pathol. 33:206–212. 2002. View Article : Google Scholar : PubMed/NCBI
25	Lévy L, Neuveut C, Renard CA, Charneau P, Branchereau S, Gauthier F, Nhieu JTV, Cherqui D, Petit-Bertron AF, Mathieu D and Buendia MA: Transcriptional activation of interleukin-8 by β-catenin-Tcf4. J Biol Chem. 277:42386–42393. 2002. View Article : Google Scholar : PubMed/NCBI
26	Austinat M, Dunsch R, Wittekind C, Tannapfel A, Gebhardt R and Gaunitz F: Correlation between β-catenin mutations and expression of Wnt-signaling target genes in hepatocellular carcinoma. Mol Cancer. 7:21–30. 2008. View Article : Google Scholar : PubMed/NCBI
27	Hamada S, Futamura N, Ikuta K, Urakawa H, Kozawa E, Ishiguro N and Nishida Y: CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for desmoid tumors: A pilot study. PLoS One. 9:e963912014. View Article : Google Scholar : PubMed/NCBI
28	An J, Woo HY, Lee Y, Kim HS, Jeong J and Kim SK: Clinicopathological features of 70 desmoid-type fibromatoses confirmed by β-catenin immunohistochemical staining and CTNNB1 mutation analysis. PLoS One. 16:e02506192021. View Article : Google Scholar : PubMed/NCBI
29	Oulès B, Mourah S, Baroudjian B, Jouenne F, Delyon J, Louveau B, Gruber A, Lebbe C and Battistella M: Clinicopathologic and molecular characterization of melanomas mutated for CTNNB1 and MAPK. Virchows Arch. 480:475–480. 2022. View Article : Google Scholar : PubMed/NCBI
30	Norkowski E, Masliah-Planchon J, Le Guellec S, Trassard M, Courrèges JB, Charron-Barra C, Terrier P, Bonvalot S, Coindre JM and Laé M: Lower rate of CTNNB1 mutations and higher rate of APC mutations in desmoid fibromatosis of the breast: A series of 134 tumors. Am J Surg Pathol. 44:1266–1273. 2020. View Article : Google Scholar : PubMed/NCBI
31	Li G, Xu D, Sun J, Zhao S and Zheng D: Paclitaxel inhibits proliferation and invasion and promotes apoptosis of breast cancer cells by blocking activation of the PI3K/AKT signaling pathway. Adv Clin Exp Med. 29:1337–1345. 2020. View Article : Google Scholar : PubMed/NCBI
32	Zhao S, Tang Y, Wang R and Najafi M: Mechanisms of cancer cell death induction by paclitaxel: An updated review. Apoptosis. 27:647–667. 2022. View Article : Google Scholar : PubMed/NCBI
33	Alalawy AI: Key genes and molecular mechanisms related to Paclitaxel Resistance. Cancer Cell Int. 24:2442024. View Article : Google Scholar : PubMed/NCBI
34	Froger A and Hall JE: Transformation of plasmid DNA into E. coli using the heat shock method. J Vis Exp. 2532007.doi: 10.3791/253. PubMed/NCBI
35	Ke X and Shen L: Molecular targeted therapy of cancer: The progress and future prospect. Front Med. 1:69–75. 2017.
36	Tarighati E, Keivan H and Mahani H: A review of prognostic and predictive biomarkers in breast cancer. Clin Exp Med. 23:1–16. 2023.PubMed/NCBI
37	Duffy MJ and Crown J: A personalized approach to cancer treatment: How biomarkers can help. Clin Chem. 54:1770–1779. 2008. View Article : Google Scholar : PubMed/NCBI
38	Beaver JA, Gustin JP, Yi KH, Rajpurohit A, Thomas M, Gilbert SF, Rosen DM, Park BH and Lauring J: PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clin Cancer Res. 19:5413–5422. 2013. View Article : Google Scholar : PubMed/NCBI
39	Welsh J: Animal models for studying prevention and treatment of breast cancer. Animal Models for the Study of Human Disease. Conn PM: Academic Press; Cambridge: pp. 997–1018. 2013, View Article : Google Scholar
40	Waks AG and Winer EP: Breast cancer treatment: A review. JAMA. 321:288–300. 2019. View Article : Google Scholar : PubMed/NCBI
41	Burguin A, Diorio C and Durocher F: Breast cancer treatments: Updates and new challenges. J Pers Med. 11:8082021. View Article : Google Scholar : PubMed/NCBI
42	Kaboli PJ, Imani S, Jomhori M and Ling KH: Chemoresistance in breast cancer: PI3K/Akt pathway inhibitors vs the current chemotherapy. Am J Cancer Res. 11:51552021.PubMed/NCBI
43	Kim MS, Jeong EG, Yoo NJ and Lee SH: Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br J Cancer. 98:1533–1535. 2008. View Article : Google Scholar : PubMed/NCBI
44	Lauring J, Park BH and Wolff AC: The phosphoinositide-3-kinase-Akt mTOR pathway as a therapeutic target in breast cancer. J Natl Compre Cancer Netw. 11:670–678. 2013. View Article : Google Scholar : PubMed/NCBI
45	Guo G, Qiu X, Wang S, Chen Y, Rothman PB, Wang Z and Chen JL: Oncogenic E17K mutation in the plekstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells. Oncogene. 29:3845–3853. 2010. View Article : Google Scholar : PubMed/NCBI
46	Yang WL, Zhang X and Lin HK: Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development. Oncogene. 29:4493–4503. 2010. View Article : Google Scholar : PubMed/NCBI
47	Yi KH, Axtmayer J, Gustin JP, Rajpurohit A and Lauring J: Functional analysis of non-hotspot AKT1 mutants found in human breast cancers identifies novel driver mutations: Implications for personalized medicine. Oncotarget. 4:29–34. 2013. View Article : Google Scholar : PubMed/NCBI
48	De Marco C, Malanga D, Rinaldo N, De Vita F, Scrima M, Lovisa S, Fabris L, Carriero MV, Franco R, Rizzuto A, et al: Mutant AKT1-E17K is oncogenic in lung epithelial cells. Oncotarget. 6:39634–39650. 2015. View Article : Google Scholar : PubMed/NCBI
49	Hasbal-Celikok G, Aksoy-Sagirli P, Altiparmak-Ulbegi G and Can A: Identification of AKT1/β-catenin mutations conferring cetuximab and chemotherapeutic drug resistance in colorectal cancer treatment. Oncol Lett. 21:1–10. 2021. View Article : Google Scholar : PubMed/NCBI
50	Davies BR, Guan N, Logie A, Crafter C, Hanson L, Jacobs V, James N, Dudley P, Jacques K, Ladd B, et al: Tumors with AKT1 E17K mutations are rational targets for single agent or combination therapy with AKT inhibitors. Mol Can Ther. 14:2441–2451. 2015. View Article : Google Scholar : PubMed/NCBI
51	Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, Bando H, El–Khoueiry AB, Pérez–Fidalgo JA, Mita A, et al: AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 35:2251–2259. 2017. View Article : Google Scholar : PubMed/NCBI
52	Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, et al: Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: The PAKT trial. J Clin Oncol. 38:423–433. 2020. View Article : Google Scholar : PubMed/NCBI
53	Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, et al: Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1 E17K-Mutant, ER-positive metastatic breast cancer. Clin Cancer Res. 26:3947–3957. 2020. View Article : Google Scholar : PubMed/NCBI
54	Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG and Hung MC: Beta-catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA. 97:4262–4266. 2000. View Article : Google Scholar : PubMed/NCBI
55	Ryo A, Nakamura M, Wulf G, Liou YC and Lu KP: Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat Cell Biol. 3:793–801. 2001. View Article : Google Scholar : PubMed/NCBI
56	Li S, Li S, Sun Y and Li L: The expression of β-catenin in different subtypes of breast cancer and its clinical significance. Tumor Biol. 35:7693–7698. 2014. View Article : Google Scholar
57	Samant C, Kale R, Pai KSR, Nandakumar K and Bhonde M: Role of Wnt/β-catenin pathway in cancer drug resistance: Insights into molecular aspects of major solid tumors. Biochem Biophys Res Commun. 729:1503482024. View Article : Google Scholar : PubMed/NCBI
58	Mukherjee N and Panda CK: Wnt/β-catenin signaling pathway as chemotherapeutic target in breast cancer: An update on pros and cons. Clin Breast Cancer. 20:361–370. 2020. View Article : Google Scholar : PubMed/NCBI
59	Ozcan G: PTCH1 and CTNNB1 emerge as pivotal predictors of resistance to neoadjuvant chemotherapy in ER+/HER2-breast cancer. Front Oncol. 13:12164382023. View Article : Google Scholar : PubMed/NCBI
60	Yoo TK, Lee WS, Kim J, Kim MK, Park IA, Kim JH and Han W: Mutational analysis of triple-negative breast cancer using targeted kinome sequencing. J Breast Cancer. 25:1642022. View Article : Google Scholar : PubMed/NCBI
61	Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A, Natrajan R and Reis-Filho JS: β-catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol. 24:209–231. 2011. View Article : Google Scholar : PubMed/NCBI