المؤلفون: Goyette, Marie-Anne^1,2,3, Stevens, Laura E.^1,2,3, DePinho, Carolyn R.¹, Seehawer, Marco^1,2,3, Nishida, Jun^1,2,3, Zheqi Li^1,2,3, Wilde, Callahan M.¹, Rong Li⁴, Xintao Qiu⁴, Pyke, Alanna L.¹, Zhao, Stephanie¹, Lim, Klothilda⁴, Tender, Gabrielle S.⁵, Northey, Jason J.⁶, Riley, Nicholas M.⁵, Long, Henry W.⁴, Bertozzi, Carolyn R.^5,7,8, Weaver, Valerie M.^{6,9,10,11,12,13}, Polyak, Kornelia^1,2,3 Kornelia_polyak@dfci.harvard.edu

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 5/14/2024, Vol. 121 Issue 20, p1-11. 19p.

مصطلحات موضوعية: *METASTATIC breast cancer, *HER2 positive breast cancer, *GLYCOPROTEIN synthesis, *PROSTATE cancer patients, *BRAIN metastasis, *CURCUMIN, *STROMAL cells

مستخلص: Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases. [ABSTRACT FROM AUTHOR]

المؤلفون: Xiaokai Ding¹, Sharko, Amanda C.¹, McDermott, Martina S. J.¹, Schools, Gary P.¹, Chumanevich, Alexander¹, Hao Ji¹, Jing Li¹, Li Zhang¹, Mack, Zachary T.¹, Sikirzhytski, Vitali¹, Shtutman, Michael¹, Ivers, Laura², O'Donovan, Norma², Crown, John², Gyõrffy, Balázs^3,4, Chen, Mengqian^1,5, Roninson, Igor B.¹, Broude, Eugenia V.¹ broude@cop.sc.edu

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 8/9/2022, Vol. 119 Issue 32, p1-11. 52p.

مصطلحات موضوعية: *HER2 positive breast cancer, *DRUG resistance, *ELECTROCONVULSIVE therapy, *PROTEIN-tyrosine kinases, *TRASTUZUMAB, *BRCA genes, *HEMOPHILIACS

مستخلص: Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2+ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2+ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and upregulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2+ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2+ BrCa. [ABSTRACT FROM AUTHOR]

المؤلفون: Tong Liu¹, New, Maria I.², Hao Zhang³, Jie Yang³, Xunyan Ou³, Yining Wang³, Tony Yuen³, Caigang Liu³, Li Sun³, Peng Liu³, Gupta, Animesh³, Abu-Amer, Wahid³, Zaidi, Mone³, Danyu Zhao³, Meisi Yan³, Zaidi, Neeha³, Izadmehr, Sudeh³, Minna Luo³, Xuefeng Bai³, Yan Wang³

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 7/18/2017, Vol. 114 Issue 29, p7683-7688. 6p.

مصطلحات موضوعية: *BREAST cancer treatment, *HER2 protein, *SPERMATOGENESIS, *GENE ontology, *GENE expression

مستخلص: Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesisrelated testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed onWestern blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy. [ABSTRACT FROM AUTHOR]

المؤلفون: Vega-Rubín-de-Celis, Silvia, Zou, Zhongju, Fernández, Álvaro F., Ci, Bo, Kim, Min, Xiao, Guanghua, Xie, Yang, Levine, Beth

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2018 Apr . 115(16), 4176-4181.

الوصول الحر: https://www.jstor.org/stable/26508837Test

المؤلفون: Floros, Konstantinos V., Lochmann, Timothy L., Hu, Bin, Monterrubio, Carles, Hughes, Mark T., Wells, Jason D., Morales, Cristina Bernadó, Ghotra, Maninderjit S., Costa, Carlotta, Souers, Andrew J., Boikos, Sosipatros A., Leverson, Joel D., Tan, Ming, Serra, Violeta, Koblinski, Jennifer E., Arribas, Joaquin, Prat, Aleix, Paré, Laia, Miller, Todd W., Dozmorov, Mikhail G., Harada, Hisashi, Windle, Brad E., Scaltriti, Maurizio, Faber, Anthony C.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2018 Mar . 115(11), E2594-E2603.

الوصول الحر: https://www.jstor.org/stable/26508360Test

المؤلفون: Jaekwang Jeong¹, VanHouten, Joshua N.¹, Dann, Pamela¹, Kim, Wonnam¹, Sullivan, Catherine², Herbert Yu³, Liotta, Lance⁴, Espina, Virginia⁴, Stern, David F.⁵, Friedmanf, Peter A.⁶, Wysolmerski, John J.¹ John.Wysolmerski@yale.edu

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 1/19/2016, Vol. 113 Issue 3, pE282-E290. 9p.

مصطلحات موضوعية: *HER2 protein, *PROTEIN kinases, *BREAST tumors, *CANCER cells, *CANCER treatment

مستخلص: In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers,where high tumor levels predict increasedmortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

المؤلفون: Austin, Cary D., Nelson, Christopher, Scheller, Richard H., Scales, Suzie J.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2005 Dec . 102(50), 17987-17992.

الوصول الحر: https://www.jstor.org/stable/4152715Test

المؤلفون: Jackson-Fisher, Amy J., Bellinger, Gary, Ramabhadran, Rajani, Morris, Jacqueline K., Lee, Kuo-Fen, Stern, David F., Brugge, Joan S.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2004 Dec 01. 101(49), 17138-17143.

الوصول الحر: https://www.jstor.org/stable/3373973Test

المؤلفون: Hu, Linshan, Liang, Shan, Chen, Hu, Lv, Tao, Wu, Junfeng, Chen, Deshi, Wu, Min, Sun, Shengnan, Zhang, Haibo, You, Han, Ji, Hongbin, Zhang, Yujun, Bergholz, Johann, Xiao, Zhi-Xiong Jim

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2017 May . 114(20), E3964-E3973.

الوصول الحر: https://www.jstor.org/stable/26483254Test

المؤلفون: Hanker, Ariella B.¹, Pfefferle, Adam D.², Balko, Justin M.^1,3, Kuba, María Gabriela⁴, Young, Christian D.¹, Sánchez, Violeta¹, Sutton, Cammie R.¹, Cheng, Hailing⁵, Perou, Charles M.^2,6, Zhao, Jean J.^5,7 jean_zhao@dfci.harvard.edu, Cook, Rebecca S.^3,8, Arteaga, Carlos L.^1,3,8 carlos.arteaga@vanderbilt.edu

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 8/27/2013, Vol. 110 Issue 35, p14372-14377. 6p.

مصطلحات موضوعية: *HER2 protein, *GENE amplification, *PHOSPHATIDYLINOSITOL 3-kinases, *GENETICS of breast cancer, *MICE genetics, *ONCOGENES, *METASTASIS, *LAPATINIB, *THERAPEUTICS

مستخلص: Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2+/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2+/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2+/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CAH1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies. [ABSTRACT FROM AUTHOR]