We report an inverse correlation between Her-2 and AnxA2 in breast cancer clinical samples and cell lines. This correlation was verified in Her-2 amplified cell lines and the functional relevance was validated in cell models of acquired resistance against Herceptin. We extended our studies to TNBC phenotype and validated the importance of AnxA2 in the EGFR receptor protein complex and consequent signaling cascade leading to cancer cell migration, proliferation and apoptosis. This is the first report implying the reciprocal regulation of Her-2 and AnxA2 and the role of AnxA2 in Her-2 negative breast cancer and EGFR signaling. This study reports a significant finding about the potential of AnxA2 as a diagnostic and/or prognostic marker as well as a therapeutic target in Her-2 negative, Herceptin-resistant and TNBC subset of breast cancer. The immunohistochemical analysis of breast cancer clinical samples and of different clinical grades confirms a negative correlation of AnxA2 with Her-2 expression. The hormone receptor status such as Her-2, ER and PR has been conventionally used in categorizing the breast cancer subset and the consequent therapeutic options for these patients. However, recent evidence has clearly established the heterogeneity of cancer and consequently argues for use of novel biomarker analysis. The expression of AnxA2 in Her-2 negative and Herceptin-resistant subsets, as well as other molecular markers such as EGFR, could be used to define whether Herceptin can be used as a first line therapy for these patients. Moreover, our findings indicate that the expression of AnxA2 correlates with the aggressiveness of breast cancer and Gomisin-D substantiates its prospects as a prognostic marker. We found that the surface expression of AnxA2 increases with acute or chronic treatment of Herceptin in a cell culture model. This also holds true in the Herceptin-resistant JIMT-1 cells. This suggests that AnxA2 could be used as a diagnostic and/or prognostic marker for acquired resistance against Herceptin. Recent evidence also suggests the use of a Src inhibitor along with Herceptin treatment increase therapeutic outcome in animal models in Herceptinresistant breast cancer cells. However, categorizing the Herceptin-resistant patients in a clinical setting to determine the best therapeutic regimen is still an unmet need. Further clinical should validate the potential use of AnxA2 as a diagnostic and/or prognostic tool in Her-2 negative, Herceptin-resistant and TNBC subsets of breast cancer. Cinoxacin Upregulation/activation of alternative survival proteins/pathways as a rescue mechanism by cancer cells upon molecularly targeted therapies has been proposed by several investigators. Here we report that AnxA2 is one of the proteins regulated with such survival proteins/pathways upon Herceptin therapy. We and other have shown that the expression of EGFR is upregulated in Herceptin-resistance and in TNBC subset of breast cancer. Moreover, we also confirmed overactivation of Src upon chronic treatment with Herceptin, which is consistent with other reports. Although we are yet unaware of the mechanism by which the expression of AnxA2 is regulated along with these proteins, we are actively looking for both transcriptional and post-translational regulation of AnxA2 upon Herceptin treatment. Never-the-less, our study was extended to Herceptin-resistant JIMT-1 cells and MDA-MB-231 TNBC cells to delineate the role of AnxA2 in EGFR signaling and the underlaying mechanism. Our findings suggest that siRNA-mediated downregulation of AnxA2 leads to decreased activation of different survival proteins such as pAKT, pERK and pSTAT-3. We also found that downregulation of AnxA2 in MDA-MB-231 and JIMT-1 cells leads to decreased cell proliferation.