Background: Of all breast cancer subtypes, the basal-type/triple-negative breast cancer (BTBC) has the worst clinical outcome. The major reasons are the highly invasive nature of the disease and the limited treatment options available to patients. As opposed to the HER2−positive and the hormone-positive breast cancers, targeted therapy against BTBC is unavailable. These premises underscore the need for discovering and characterizing drug targets in BTBC. In this study, we have focused on the Src homology phosphotyrosyl phosphatase 2 (SHP) which seems to play pivotal roles in BTBC. The major reason for focusing on SHP2 is that it is an essential downstream effector of mitogenic and cell survival signaling downstream of receptor tyrosine kinases such as EGFR (HER1) and IGF-1R, and the cytoplasmic tyrosine kinase Src, which are known to be elevated in BTBC. Materials and Methods: The state of SHP2 and EGFR expression in BTBC tumors was determined by immunohistochemistry. The functional significance of SHP2 in BTBC cells was investigated by ablating its expression with specific shRNA and then assessing impact on mitogenic and cell survival signaling using immunoblotting with phospho-specific antibodies, effect on transformation using 3D cultures such as growth in soft agar and matrigel, consequence on cell motility and invasiveness using florescent-tagged matrigel. Furthermore, the impact of SHP2 inhibition on tumorigenesis was tested by intramammary transplantation in vivo and monitoring and analyzing tumor growth and metastasis. Results: We have shown that the SHP2 protein is elevated in BTBC tumors. More importantly, the elevated expression of SHP2 is highly correlated with overexpression of the EGFR (HER1), suggesting their potential synergistic role to promote BTBC. Inhibition of SHP2 in BTBC cells reversed transformation and suppressed proliferation, indicating their dependence on the function of SHP2. Moreover, inhibition of SHP2 abolished EGF-induced mitogenic and cell survival signaling, which is in agreement with its role in cell proliferation and transformation. More dramatic was that the invasive phenotype of BTBC cells in 3D matrigel was completely blocked by inhibition of SHP2, suggesting that the invasive property of these cells is dependent on SHP2. Even more dramatic was that the tumorigenic and metastatic potential of BTBC cells was abolished by SHP2 inhibition. Discussion: The current study demonstrates that SHP2 plays a pivotal role in promoting BTBC. Given that SHP2 is a tyrosine phosphatase with positive signaling role, its promotion of BTBC must occurs through promotion of tyrosine kinase signaling. Together, our results provide the first glimpse on the potential of SHP2 as a drug target in BTBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-15.

The basal-type/triple-negative breast cancer (BTBC) has the worst clinical outcome primarily because of its invasive nature and lack of targeted therapy. In addition, BTBC is more prevalent in younger African-American women. Therefore, there is an urgent need for discovering and characterizing potential drug targets for BTBC. In this study, we have focused on the Src homology phosphotyrosyl phosphatase 2 (SHP) which seems to play critical roles in promoting BTBC. The major reason for focusing on SHP2 is its positive role in mitogenic and cell survival signaling induced by receptor tyrosine kinases such as EGFR (HER1), PDGFR, IGF-1R, and the cytoplasmic tyrosine kinase Src, which are known to be elevated in BTBC. Here, we have shown that the SHP2 protein is elevated in approximately seventy percent of BTBC tumors, and is highly correlated with overexpression of the EGFR (HER1), suggesting their potential synergistic role to promote BTBC. Functional studies demonstrated that SHP2 is essential for EGF-induced mitogenic and cell survival signaling and for maintenance of the transformed phenotype in BTBC cells. More dramatic was that the invasive phenotype of BTBC cells in 3D matrigel was completely blocked by inhibition of SHP2, suggesting that the invasive property of these cells is dependent on SHP2. Even more dramatic was that the tumorigenic and metastatic potential of BTBC cells was abolished by SHP2 inhibition. These results show that SHP2 has untapped potential to serve as a drug target in BTBC. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B69.

The Src homology phosphotyrosyl phosphatase 2 (SHP2) plays a positive role in receptor tyrosine kinase-induced mitogenic and cell survival signaling. In addition, SHP2 mediates cell transformation induced by oncogenic tyrosine kinases. Here, we provide evidence that show that the SHP2 protein is overexpressed in basal-type/triple-negative breast cancer (BTBC) with strong correlation to higher tumor grade, metastasis and elevated expression of the epidermal growth factor. We further show that SHP2 plays an essential role in the tumorigenesis and metastasis of BTBC cells (MDA-MB-231 and MDA-MB-468) transplanted into the mammary glands of NOD/SCID mice. These results suggest that SHP2 can be used for targeted therapy in BTBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 238. doi:10.1158/1538-7445.AM2011-238

One of the factors that contribute to the disproportionately high mortalities in basal-like and triple-negative breast cancer (BTBC) is the lack of targeted therapies. Identifying and characterizing potential targets is therefore critical for future development of such therapies. In the current report, we show that silencing the expression of the Src homology phosphotyrosyl phosphatase 2 (SHP2) in BTBC cell lines (MDA-MB231 and MDA-MB468) suppresses cell proliferation, reverses transformation, and blocks invasiveness. Unexpectedly, we have discovered that inhibition of SHP2 induces basal-to-luminal transition (BLT) in BTBC cells as evidenced by a decrease in the expression of mesenchymal markers and/or drivers (vimentin, ZEB1, Snail, and alpha smooth muscle actin) and an increase in the expression of the luminal marker cytokeratin 18. Furthermore, we have discovered that inhibition of SHP2 induces the expression of the estrogen receptor alpha in otherwise triple-negative breast cancer cells. Intramammary transplantation studies in the NOD/SCID mice demonstrated that inhibition of SHP2 suppresses tumorigenesis and blocks metastasis. Analyses of total cell lysates prepared from cells grown in 3D matrigel cultures demonstrated that SHP2 mediates the activation of the Ras-ERK, the PI3K, and the β-catenin signaling pathways to promote the tumorigenic, invasive, and metastatic potential of BTBC cells. By and large, the results presented in this report suggest that SHP2 plays an essential role in the biology of BTBC. Citation Format: Fatimah Matalka, Hua Zhao, Yehenew M. Agazie. Inhibition of SHP2 in basal-like and triple-negative breast cancer cells induces basal-to-luminal transition, suppresses tumorigenesis, and blocks metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-280. doi:10.1158/1538-7445.AM2013-LB-280