Therapeutic targeting of CD24 may enhance the efﬁcacy of targeted agents, such as trastuzumab and lapatinib, in treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a team of researchers led by Mari Hosonaga, MD, of the Department of Breast Oncology, Tokyo Medical University Hospital, Japan.
Therapeutic targeting of CD24 may enhance the efï¬cacy of targeted agents, such as trastuzumab and lapatinib, in treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to a team of researchers led by Mari Hosonaga, MD, of the Department of Breast Oncology, Tokyo Medical University Hospital, Japan.
The investigators noted that although combined therapy using a targeted agent with adjuvant chemotherapy improves survival rates in early-stage HER2-overexpressing breast cancer, approximately 15% of patients relapse, and more than 70% of patients with HER2-positive metastatic breast cancer show resistance to HER2-targeted therapy within 1 year. “Indicators that identify such resistant tumors are thus needed to optimize treatment strategies,” they explained in a report published in the July issue of Cancer Science.
Although CD24 is understood to be a marker of differentiated normal mammary epithelial cells, overexpression of the gene is associated with a poor prognosis in breast cancer. Because HER2-positive breast cancer has a predominantly CD24-positive status, “we wondered whether co-expression of CD24 with HER2 might be associated with therapeutic resistance of HER2-positive cells.”
To investigate the relevance of CD24 expression in HER2-positive breast cancer, they established HER2-expressing cell lines by introducing an expression vector for HER2 into MDA-MB-231-Luc, a human breast cancer cell line that is triple-negative for the estrogen receptor, the progesterone receptor and HER2, and which has been engineered to express luciferase. Two lines of 231-Luc cells were obtained and immunoblot analysis was used to assess expression of HER2 and activation of HER2 signaling. Phosphorylation levels of HER2 and Akt increased in a manner dependent on the proportion of HER2-positive cells, whereas the phosphorylation of extracellular-signal-regulated kinase (Erk) 1⁄2 was not affected by ectopic expression of HER2.
“All our data suggest that HER2-positive cells have advantages in survival under the co-expression of CD24 through the phosphorylation of Akt,” the investigators reported. “In other words, HER2+/CD24+ cells might be selected with an advantage in growth and survival.”
Finally, the authors examined whether knockdown of CD24 might increase the sensitivity of breast cancer cells to HER2-targeted therapy. “Treatment of CD24-depleted or control BT-474 cells with lapatinib, a dual tyrosine kinase inhibitor for both the epidermal growth factor receptor and HER2, revealed that knockdown of CD24, indeed, enhanced the antiproliferative and death-promoting effects of lapatinib,” they reported. They also found that knockdown of CD24 increased the sensitivity of lapatinib-resistent cells to the antiproliferative and death-promoting effects of lapatinib. “These data thus suggest that expression of CD24 supports HER2-dependent cancer cell survival.
“Our results indicate that CD24 plays an important role in regulating HER2-initiated survival signaling in breast cancer cells,” the investigators concluded. “We found a positive association between HER2 and CD24 expression, and that expression of CD24 supports the HER2-PI3K-Akt signaling pathway in HER2-positive breast cancer cells. Given that depletion of CD24 increased the size of the HER2-negative cell subpopulation and suppressed Akt phosphorylation, we suggest that CD24 positively regulates HER2-Akt signaling and thereby promotes resistance to HER2-targeted therapy and consequent tumor progression. Therapeutic targeting of CD24 might thus be expected to enhance the efï¬cacy of HER2-targeted agents.”