Does PTEN Loss and Activation of the mTOR Pathway Underlie Breast Cancer Metastases?
Rui Zheng, Ashley Cimino-Mathews, Bora Gurel, Angelo M De Marzo, Jessica Hicks, Pedram Argani. Johns Hopkins, Baltimore, MD
Background: Loss of tumor suppressor gene PTEN results in hyperactivation of PI3K/AKT/mTOR pathway, leading to uncontrolled proliferation and survival. In experimental models of breast cancer, PTEN loss has been associated with resistance to targeted therapy (trastuzumab in Her2-positive tumors, tamoxifen in ER-positive tumors). However, the status of PTEN and downstream targets pmTOR and pS6 in primary breast carcinomas (PBC) and matched metastatic breast carcinomas (MBC) has not been assessed.
Design: Tissue microarrays (TMAs) were constructed from archived paraffin tissue blocks of PBCs and resected matched MBCs from 16 individual patients. TMAs were labeled by immunohistochemistry (IHC) for ER, PR, and Her2 to classify cases into luminal A (ER/PR+, Her2-), triple negative (TNC) (ER/PR/Her2-), or Her2 (ER/PR-, Her2+). These 3 TMAs, comprising 270 tumor spots from 32 specimens, were labeled by IHC for PTEN, pmTOR and pS6. PTEN labeling was scored as absent (which correlates well with PTEN gene deletion), reduced, or intact. Intensity of pmTOR and pS6 labeling were graded as 0 – 3 (0 = no labeling, 1 = weak, 2 = moderate, 3 = strong). A H-score for pmTOR and pS6 labeling was calculated by multiplying the intensity by percentage of immunoreactive neoplastic cells.
Results: The cohort (n = 16) included 8 luminal A, 6 TNC, and 2 Her2 cases. Two of 16 cases (12.5%) demonstrated PTEN loss in both PBC and the corresponding MBC. One out of 16 cases (6.25%) demonstrated detectable PTEN expression in the PBC and loss of PTEN expression in the corresponding MBC; in this case, there was an almost 4 fold increase of pS6 labeling and 2 fold increase of pmTOR labeling in the MBC compared with the PBC. All 3 of these cases were TNC. The remaining 13 cases (13 of 16, 81.25%) retained PTEN expression in both PBC and MBC. PTEN labeling did not correlate with pmTOR or pS6 labeling; however, there was a significant increase in labeling of pS6 (p = 0.005) in MBC (mean H-score = 105.9) versus PBC (mean H-score = 40.4), and a trend towards increased labeling of pmTOR (p = 0.074) in MBC (mean H-score = 123.7) versus PBC (mean H-score = 79.1).
Conclusions: PTEN loss from PBC to MBC is uncommon, and in this study PTEN loss was limited to TNC and not PBC which proved to be resistant to targeted therapy (luminal A and Her2 cases). The increased labeling for pmTOR and pS6 in MBC likely reflects increased mTOR pathway activation, which may reflect increased metastatic potential of clones with pathway activation or selection for increased pathway signaling by systemic therapy. Regardless, these results support targeting of the mTOR pathway in MBC.
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 8, Wednesday Afternoon