Abstract
Proton therapy offers a distinct physical advantage over conventional X-ray therapy, but its biological advantages remain understudied. In this study, we aimed to identify genetic factors that contribute to proton sensitivity in breast cancer (BC). Therefore, we screened relative biological effectiveness (RBE) of 230 MeV protons, compared to 6 MV X-rays, in ten human BC cell lines, including five triple-negative breast cancer (TNBC) cell lines. Clonogenic survival assays revealed a wide range of proton RBE across the BC cell lines, with one out of ten BC cell lines having an RBE significantly different from the traditional generic RBE of 1.1. An abundance of cyclin D1 was associated with proton RBE. Downregulation of RB1 by siRNA or a CDK4/6 inhibitor increased proton sensitivity but not proton RBE. Instead, the depletion of cyclin D1 increased proton RBE in two TNBC cell lines, including MDA-MB-231 and Hs578T cells. Conversely, overexpression of cyclin D1 decreased the proton RBE in cyclin D1-deficient BT-549 cells. The depletion of cyclin D1 impaired proton-induced RAD51 foci formation in MDA-MB-231 cells. Taken together, this study provides important clues about the cyclin D1-CDK4-RB1 pathway as a potential target for proton beam therapy in TNBC.
Highlights
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide, and it continues to be one of the leading causes of cancer-related deaths
We investigated the cyclin D1/CDK4/RB1 pathway in three Triple-negative breast cancer (TNBC) cell lines, MDA-MB-231, Hs578T, and BT-549 cells, which had different RBE10 values (Figure 2A), and found that BT-549 cells had a pattern of expression for RB1 pathway proteins distinct from those of Hs578T and MDA-MB-231 cells, with the loss of RB1 and cyclin D1 and high expression of CDK4 and CDKN2A (Figure 2B)
Based on previous preclinical studies that protons may be more effective than photons for homologous recombination (HR)-deficient cancers, we aimed to investigate the biological effect of proton therapy on TNBC management
Summary
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide, and it continues to be one of the leading causes of cancer-related deaths. The standard treatment for BC combines surgery, radiotherapy, chemotherapy, and hormone therapy, depending on the stage, grade, and molecular subtype of the tumor. Adjuvant radiotherapy following mastectomy or lumpectomy is routinely used because it reduces cancer recurrence [1,2]. Triple-negative breast cancer (TNBC) is a BC subtype that lacks the estrogen receptor (ER), progesterone receptor (PR), and overexpression of human epidermal growth factor receptor 2 (HER2) [3]. Platinum-based chemotherapy remains the mainstay for treatment because no targeted therapy is available for TNBC. Whether the benefit of radiotherapy varies by molecular subtype remains unknown [4]. Mutations in BRCA1, a tumor suppressor gene that is involved in DNA damage repair, such as homologous recombination (HR), are prevalent in TNBC patients. “BRCA-ness,” which refers to the biological characteristics of altered BRCA functionality without BRCA mutations, is predominantly detected in TNBC, compared to other BC types [5]
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