Estrogen receptor-positive (ER+) breast cancer cells in Black women have significantly different patterns of DNA damage repair (DDR) signaling than in White women, leading to increased resistance to endocrine therapies and higher mortality, according to a new study led by researchers at the Sanford Burnham Prebys (SBP) Medical Discovery Institute in La Jolla, Calif.
The findings, published in the February 9, 2022 issue of Therapeutic Advances in Medical Oncology, reveal a potential biomarker signature tailored to the unique molecular biology of breast cancer in Black women (doi: 10.1177/17588359221075458).
Once this signature is validated, it could indicate earlier treatment with cell cycle inhibitors (CDK4/6 inhibitors) in combination with standard care for Black breast cancer patients, potentially improving their outcomes, the study suggests. Currently, clinical diagnostics for breast cancer are mainly based on data from White women.
"DNA repair pathways are the first line of defense for each cell in the body and these pathways stop cells from acquiring mutations that could lead to the development of cancer," said Svasti Haricharan, PhD, Assistant Professor with the Aging, Cancer, and Immuno-oncology program at SBP, and the study's corresponding author.
"We show in this study that these proteins have unique patterns of behavior in breast cells of Black women, and that this is therapeutically significant," added Aloran Mazumder, PhD, a postdoctoral researcher at SBP and the first author of the study.
Although the incidence of ER+ breast cancer among Black women is comparable to White women, Black women are 42 percent more likely to die from their disease than White women. Even when controlled for access to health care, environment, lifestyle, and socioeconomic factors, differences in presentation and outcome in Black women persist, suggesting that underlying molecular biology may constitute a root cause.
Recent studies mainly conducted on White patients with ER+ breast cancer have demonstrated that loss of DNA repair can drive resistance to standard endocrine therapies-such as tamoxifen and aromatase inhibitors-that contributes to poor outcome in about a quarter of these patients. Specifically, the research identified defects of mismatch (MMR), nucleotide excision repair (NER), and base excision repair (BER) pathways as primary causes of endocrine therapy resistance.
All these pathways help restore damaged DNA to its original base sequence so that DNA can carry out its fundamental job: to be replicated and copied into a sister molecule, RNA, for the manufacture of proteins and other tasks. The 2015 Nobel Prize in Chemistry was awarded to three scientists for their work on the mechanisms of DNA repair.
That said, little has been revealed about DNA repair patterns linked to treatment resistance among non-White women with ER+ breast cancer, particularly Black and Hispanic women, due to their "systemic exclusion" from biomedical studies, according to Haricharan.
"For this study, we wanted to see whether breast cancer cells in Black and White patients share similar patterns of DNA repair activity or if the DNA repair biology in Black women is different, and how it associates with survival," she said.
Study Details
To address this knowledge gap, Haricharan and team compared the regulation of more than 100 DNA repair proteins among breast cancer cells in Black and White women, using a discovery dataset that included 51 Black patients and two publicly available validation datasets (TCGA and GSE50939, which contain 49 and 44 Black patients, respectively). Two other datasets with normal breast tissue (26 Black women) were also analyzed for DNA repair patterns.
In all, about a handful of proteins were regulated differently in the breast cancer cells of Black women, all associating with changes in how rapidly these cells proliferate, which contributes to significantly worse outcomes. Namely, the researchers reported a new pattern of DNA repair signaling with lower levels of BER gene expression and simultaneously higher levels of homologous recombination (HR) gene expression in ER+ breast cancer cells in Black women. All these differently regulated genes serve as scaffolds for proteins that inhibit the cell cycle.
"By serving as scaffolds for cell cycle checkpoint kinases, these DDR proteins promote activation of checkpoints that stop the cell cycle and eventually kill cancer cells," said Haricharan. "Therefore, when levels of expression of these genes are either very high or very low, as we see in the tumors of Black women, standard care therapies are unable to induce cell cycle arrest in cancer cells, which results in therapeutic resistance."
Haricharan noted that these results represent the "first systematic examination" of DDR patterns in the tumors of Black women and constitute a first step to understanding the molecular biology specific to breast cancer in Black women.
Though not surprised that the molecular journey of breast cancer cells was found to be different between Black and White women, the researchers were surprised to find DDR patterns unique to the normal breast tissue of Black women.
That said, Haricharan cautioned about "over-interpreting the results" due to the small sample size.
"Because of the small sample size, we have likely identified low-hanging fruit-differences with the largest impact which are most likely to be consistent across multiple datasets even when looking at small numbers," Haricharan said. "This is, therefore, most likely only the tip of the iceberg and we anticipate finding many more changes when looking at larger datasets, which will then build a more accurate landscape of DNA repair in Black women."
As for next steps, Haricharan said she is creating a large multi-omics database of ER+ breast tumors from Black women in collaboration with the VA and Stephen Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle, and Co-Director of the Cancer Genetics and Prevention Program at Cedars-Sinai Medica Center in Los Angeles. Their goal is to identify and validate drivers of resistance to standard therapy that are tailored to the molecular biology of cancers arising in Black women.
"Studying the molecular biology of cancer in different cohorts of people is critical to implement personalized medicine for everyone, not just for White people, and should be a major focus of funding by the NIH moving forward," Haricharan added. "Such research is currently woefully under-funded and has led to a complete lack of understanding of the normal molecular biology of anyone who isn't White."
Warren Froelich is a contributing writer.