Search

Abstract Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1, the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC). PAMIP1 expression significantly declined in post-NAC in the two sets, and in our cohort, 75% of the samples exhibited a downregulation in NOXA post-NAC. Matched samples that showed a decline in NOXA post-NAC were examined for TIS based on a signature of downregulated expression of Lamin-B1 and Ki-67 and increased p16INK4a, and the majority exhibited a decrease in Lamin B1 (66%) and Ki-67 (80%), and increased p16INK4a (49%). Since our cohort consisted of patients that did not develop complete pathological response, such findings have clinical implications on the role of TIS and NOXA downregulation in mediating suboptimal responses to the currently established NAC.

Senescence is a major response to cancer chemotherapy and has been linked to unfavorable therapy outcomes. Lamin B1 is a component of the nuclear lamina that plays a pivotal role in chromatin stability. Downregulation of lamin B1 represents an established biomarker for cellular senescence. However, the protein expression level of lamin B1 in malignant tissue, particularly of the breast, has not been previously described. In this work, we investigated lamin B1 protein expression in normal breast epithelium, malignant breast tissue (including adjacent non-malignant tissue) and in malignant tissue exposed to neoadjuvant chemotherapy (NAC) using immunohistochemistry (IHC) in three patient groups (n = 15, n = 87, and n = 43, respectively). Our results indicate that lamin B1 mean positive expression was 93% in normal breast epithelium and 88% in malignant breast cells, but significantly decreased (mean: 55%, p < 0.001) in malignant breast tissue after exposure to NAC, suggestive of senescence induction. No significant association between lamin B1 expression and other clinicopathological characteristics or survival of breast cancer patients was recorded. To our knowledge, this is the first report that established the baseline protein expression level of lamin B1 in normal and malignant breast tissue, and its reduction following exposure to chemotherapy. In conclusion, lamin B1 downregulation can be used reliably as a component of multiple biomarker batteries to identify therapy-induced senescence (TIS) in clinical cancer.