NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy

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.

A Conversation with ChatGPT on Contentious Issues in Senescence and Cancer Research

“…Of these, the most robust evidence arises from studies that measured multiple senescence-associated markers simultaneously, which is suggested by ChatGPT as a methodological necessity in this response. For example, a three-marker signature of Lamin B1, Ki67, and p16 INK4a , showed that TIS is evident in roughly 40% of breast tumor samples exposed to neoadjuvant chemotherapy (Al Shboul et al, 2023;El-Sadoni et al, 2023). It is logical that this approach was missed by ChatGPT due to its availability only after the last update of the AI platform.…”

In Vitro Investigation of Therapy-Induced Senescence and Senescence Escape in Breast Cancer Cells Using Novel Flow Cytometry-Based Methods

“…A wide range of chemotherapeutic drugs has been reported to induce senescence in vitro in breast cancer cells, such as doxorubicin, etoposides, irinotecan, methotrexate, paclitaxel, cisplatin, 5-fluorouracil and palbociclib [8][9][10][11][12][13]. Moreover, the induction of senescence has been detected in tumour tissues of breast cancer patients after receiving chemotherapy, indicating that senescence is a clinically relevant response to cancer therapy [14][15][16][17]. In early experiments, therapy-induced senescence (TIS) was considered to have a beneficial function in cancer treatment.…”