NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis
Leontovich, Alexey A.; Jalalirad, Mohammad; Salisbury, Jeffrey L.; Mills, Lisa; Haddox, Candace; Schroeder, Mark; Tuma, Ann; Guicciardi, Maria E.; Zammataro, Luca; Gambino, Mario W.; Amato, Angela; Di Leonardo, Aldo; McCubrey, James; Lange, Carol A.; Liu, Minetta; Haddad, Tufia; Goetz, Matthew; Boughey, Judy; Sarkaria, Jann; Wang, Liewei; Ingle, James N.; Galanis, Evanthia; D’Assoro, Antonino B.
Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+ and TNBC models. ERα+ breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhigh phenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.
Leontovich, Alexey A., & Jalalirad, Mohammad, & Salisbury, Jeffrey L., & Mills, Lisa, & Haddox, Candace, & Schroeder, Mark, & Tuma, Ann, & Guicciardi, Maria E., & Zammataro, Luca, & Gambino, Mario W., & Amato, Angela, & Di Leonardo, Aldo, & McCubrey, James, & Lange, Carol A., & Liu, Minetta, & Haddad, Tufia, & Goetz, Matthew, & Boughey, Judy, & Sarkaria, Jann, & Wang, Liewei, & Ingle, James N., & Galanis, Evanthia, & D’Assoro, Antonino B.. (September 2018). NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis. Breast Cancer Research, (20:1), p.105. Retrieved from http://hdl.handle.net/10342/7788
Leontovich, Alexey A., and Jalalirad, Mohammad, and Salisbury, Jeffrey L., and Mills, Lisa, and Haddox, Candace, and Schroeder, Mark, and Tuma, Ann, and Guicciardi, Maria E., and Zammataro, Luca, and Gambino, Mario W., and Amato, Angela, and Di Leonardo, Aldo, and McCubrey, James, and Lange, Carol A., and Liu, Minetta, and Haddad, Tufia, and Goetz, Matthew, and Boughey, Judy, and Sarkaria, Jann, and Wang, Liewei, and Ingle, James N., and Galanis, Evanthia, and D’Assoro, Antonino B.. "NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis". Breast Cancer Research. 20:1. (105.), September 2018. October 24, 2020. http://hdl.handle.net/10342/7788.
Leontovich, Alexey A. and Jalalirad, Mohammad and Salisbury, Jeffrey L. and Mills, Lisa and Haddox, Candace and Schroeder, Mark and Tuma, Ann and Guicciardi, Maria E. and Zammataro, Luca and Gambino, Mario W. and Amato, Angela and Di Leonardo, Aldo and McCubrey, James and Lange, Carol A. and Liu, Minetta and Haddad, Tufia and Goetz, Matthew and Boughey, Judy and Sarkaria, Jann and Wang, Liewei and Ingle, James N. and Galanis, Evanthia and D’Assoro, Antonino B., "NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis," Breast Cancer Research 20, no. 1 (September 2018), http://hdl.handle.net/10342/7788 (accessed October 24, 2020).
Leontovich, Alexey A., Jalalirad, Mohammad, Salisbury, Jeffrey L., Mills, Lisa, Haddox, Candace, Schroeder, Mark, Tuma, Ann, Guicciardi, Maria E., Zammataro, Luca, Gambino, Mario W., Amato, Angela, Di Leonardo, Aldo, McCubrey, James, Lange, Carol A., Liu, Minetta, Haddad, Tufia, Goetz, Matthew, Boughey, Judy, Sarkaria, Jann, Wang, Liewei, Ingle, James N., Galanis, Evanthia, D’Assoro, Antonino B.. NOTCH3 Expression Is Linked to Breast Cancer Seeding and Distant Metastasis. Breast Cancer Research. September 2018; 20(1) 105. http://hdl.handle.net/10342/7788. Accessed October 24, 2020.