{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T22:38:14Z","timestamp":1788043094438,"version":"build-2784847793"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Cancer Society\u2014Research Scholar Grant","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]},{"name":"Navari Family Foundation","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]},{"name":"Indiana CTSI","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]},{"name":"NIH","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]},{"name":"NCATS","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]},{"name":"Indiana University School of Medicine\u2014South Bend","award":["#UL1 TR001108"],"award-info":[{"award-number":["#UL1 TR001108"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) patients are treated with traditional chemotherapy, such as the taxane class of drugs. One such drug, paclitaxel (PTX), can be effective in treating TNBC; however, many tumors will develop drug resistance, which can lead to recurrence. In order to improve patient outcomes and survival, there lies a critical need to understand the mechanism behind drug resistance. Our lab made the novel observation that decreased expression of the Adenomatous Polyposis Coli (APC) tumor suppressor using shRNA caused PTX resistance in the human TNBC cell line MDA-MB-157. In cells lacking APC, induction of apoptosis by PTX was decreased, which was measured through cleaved caspase 3 and annexin\/PI staining. The current study demonstrates that CRISPR-mediated APC knockout in two other TNBC lines, MDA-MB-231 and SUM159, leads to PTX resistance. In addition, the cellular consequences and molecular mechanisms behind APC-mediated PTX response have been investigated through analysis of the BCL-2 family of proteins. We found a significant increase in the tumor-initiating cell population and increased expression of the pro-survival family member Bcl-2, which is widely known for its oncogenic behavior. ABT-199 (Venetoclax), is a BH3 mimetic that specifically targets Bcl-2. ABT-199 has been used as a single or combination therapy in multiple hematologic malignancies and has shown promise in multiple subtypes of breast cancer. To address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance, we combined treatment of PTX and ABT-199. This combination treatment of CRISPR-mediated APC knockout MDA-MB-231 cells resulted in alterations in apoptosis, suggesting that Bcl-2 inhibition restores PTX sensitivity in APC knockout breast cancer cells. Our studies are the first to show that Bcl-2 functional inhibition restores PTX sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC.<\/jats:p>","DOI":"10.3390\/ijms25126745","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T03:46:29Z","timestamp":1718855189000},"page":"6745","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Bcl-2 Up-Regulation Mediates Taxane Resistance Downstream of APC Loss"],"prefix":"10.3390","volume":"25","author":[{"given":"Angelique R.","family":"Wise","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Maloney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Hering","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Zabala","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8087-9269","authenticated-orcid":false,"given":"Grace E.","family":"Richmond","sequence":"additional","affiliation":[{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"},{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica K.","family":"VanKlompenberg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6209-5274","authenticated-orcid":false,"given":"Murlidharan T.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Biology, Indiana University\u2014South Bend, South Bend, IN 46634, USA"},{"name":"Department of Computer Science and Informatics, Indiana University\u2014South Bend, South Bend, IN 46634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenifer R.","family":"Prosperi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Indiana University School of Medicine South Bend, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, South Bend, IN 46617, USA"},{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1158\/1078-0432.CCR-07-1658","article-title":"Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype","volume":"14","author":"Cheang","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.5858\/arpa.2012-0439-RA","article-title":"Basal-like breast cancer: Update on clinicopathologic, immunohistochemical, and molecular features","volume":"138","author":"Leidy","year":"2014","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1038\/sj.onc.1204455","article-title":"Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival","volume":"20","author":"Brabender","year":"2001","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"960","DOI":"10.4161\/cbt.3.10.1113","article-title":"APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q","volume":"3","author":"Arnold","year":"2004","journal-title":"Cancer Biol. Ther."},{"key":"ref_5","first-page":"4366","article-title":"Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer","volume":"60","author":"Esteller","year":"2000","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1054\/bjoc.2001.1853","article-title":"Adenomatous polyposis coli (APC) gene promoter hypermethylation in primary breast cancers","volume":"85","author":"Jin","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_7","first-page":"1998","article-title":"Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas","volume":"7","author":"Virmani","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.3892\/ol.2017.6455","article-title":"Correlation between the methylation of APC gene promoter and colon cancer","volume":"14","author":"Li","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/ijc.11197","article-title":"Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: Relationships with abnormal E-cadherin and catenin expression and microsatellite instability","volume":"106","author":"Sarrio","year":"2003","journal-title":"Int. J. Cancer J. Int. Du Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6189","DOI":"10.1158\/1078-0432.CCR-04-0597","article-title":"Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients","volume":"10","author":"Dulaimi","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.1038\/onc.2011.148","article-title":"miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo","volume":"30","author":"Holleman","year":"2011","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.ccr.2014.03.006","article-title":"MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer","volume":"25","author":"Valeri","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5795","DOI":"10.1158\/0008-5472.CAN-08-0951","article-title":"Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer","volume":"68","author":"Nagel","year":"2008","journal-title":"Cancer Res."},{"key":"ref_14","first-page":"1623","article-title":"miR-135 regulated breast cancer proliferation and epithelial-mesenchymal transition acts by the Wnt\/beta-catenin signaling pathway","volume":"43","author":"Jiang","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","first-page":"3269","article-title":"Clinicopathological significance and function of miR-135b in the occurrence and development of gastric cancer","volume":"92","author":"Wang","year":"2012","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1349-7006.2011.02131.x","article-title":"Subtype-specific alterations of the Wnt signaling pathway in breast cancer: Clinical and prognostic significance","volume":"103","author":"Mukherjee","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Stefanski, C.D., Arnason, A., Maloney, S., Kotsen, J., Powers, E., Zhang, J.T., and Prosperi, J.R. (2023). APC Loss Prevents Doxorubicin-Induced Cell Death by Increasing Drug Efflux and a Chemoresistant Cell Population in Breast Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087621"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.neo.2017.05.002","article-title":"UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses","volume":"19","author":"Chandrashekar","year":"2017","journal-title":"Neoplasia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.neo.2022.01.001","article-title":"UALCAN: An update to the integrated cancer data analysis platform","volume":"25","author":"Chandrashekar","year":"2022","journal-title":"Neoplasia"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"VanKlompenberg, M.K., Bedalov, C.O., Soto, K.F., and Prosperi, J.R. (2015). APC selectively mediates response to chemotherapeutic agents in breast cancer. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1456-x"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13820","DOI":"10.1073\/pnas.0905718106","article-title":"Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features","volume":"106","author":"Creighton","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Astarita, E.M., Maloney, S.M., Hoover, C.A., Berkeley, B.J., VanKlompenberg, M.K., Nair, T.M., and Prosperi, J.R. (2021). Adenomatous Polyposis Coli loss controls cell cycle regulators and response to paclitaxel in MDA-MB-157 metaplastic breast cancer cells. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255738"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Prosperi, J.R., Khramtsov, A.I., Khramtsova, G.F., and Goss, K.H. (2011). Apc mutation enhances PyMT-induced mammary tumorigenesis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029339"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.stemcr.2017.03.026","article-title":"Resistance to Taxanes in Triple-Negative Breast Cancer Associates with the Dynamics of a CD49f+ Tumor-Initiating Population","volume":"8","author":"Palafox","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.drup.2010.08.001","article-title":"The role of tumor initiating cells in drug resistance of breast cancer: Implications for future therapeutic approaches","volume":"13","author":"Lacerda","year":"2010","journal-title":"Drug Resist. Updat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102868","DOI":"10.18632\/oncotarget.22263","article-title":"APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation","volume":"8","author":"VanKlompenberg","year":"2017","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Maloney, S.M., Hoover, C.A., Morejon-Lasso, L.V., and Prosperi, J.R. (2020). Mechanisms of Taxane Resistance. Cancers, 12.","DOI":"10.3390\/cancers12113323"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41698-019-0084-3","article-title":"Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types","volume":"3","author":"Zilberberg","year":"2019","journal-title":"NPJ Precis. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1158\/2159-8290.CD-18-1151","article-title":"A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer","volume":"9","author":"Lok","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1158\/1078-0432.CCR-21-3811","article-title":"VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4\/6 Inhibitors-Efficacy, Safety, and Biomarker Results","volume":"28","author":"Lindeman","year":"2022","journal-title":"Clin Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nat. 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