August 16, 2023 | In a surprising twist, researchers at Sanford Burnham Prebys have found that both age and sex may matter a great deal when it comes to the consequences of many types of cancer. The culprit appears to be a problem with cell cycle regulation, as was previously seen when looking at disparities in outcome between black and white women with breast cancer, according to Svasti Haricharan, Ph.D., co-director and assistant professor in the Cancer Genome and Epigenetics Program.
In a research article that published recently in Science Advances (DOI: 10.1126/sciadv.adf2860), Haricharan and her colleagues explored the impact of mutations in the genes involved in cell replication on the treatment response of women with estrogen receptor-positive (ER+) human epidermal growth factor (HER)2− and triple-negative breast cancer (TNBC). The “weird thing” was seeing that those effects looked different in younger than older women, says Haricharan.
On a hunch, the research team then analyzed the effects of cell cycle mutations on patient outcomes in other types of cancer in both sexes. In many cases, she says, the mode of cell cycle dysregulation is significant for cancer in women but less so for cancer in men.
In cancers that affect both sexes—a list that includes brain, colorectal, liver, and lung cancers—the cell cycle regulator effects on patients relapsing while on treatment, having recurrent cancer, or dying from the disease were much more pronounced in women even for the same tumor type, Haricharan says. “Some of the associations actually appear to be unique to women.”
This may well represent a turning point in how cancer patients are treated, says Haricharan, noting that “precision medicine can only work if we take into account the whole person and not just a subset of the cancer cells that are in them.” Perhaps the reason there are no cures for cancer and fewer than desired life-sparing therapies is because scientists typically control for “confounding factors” such as age, sex, and pregnancy.
That evolution would begin with cancer researchers moving beyond cells in a dish or even cells in a mouse to consider complex human host factors that affect how a tumor grows and responds to treatment. Haricharan’s preferred tactic is to marry patient data and sophisticated genetic testing methodologies to answer knotty problems, such as how tumors form and a disease progresses.
‘Complexity of Experience’
Interest in cell cycle dysregulation was piqued by an earlier study about disparities in cancer outcomes where the focus was on race and ethnicity, says Haricharan. Specifically, she and her colleagues were looking for molecular differences in breast cancers that might explain why black women are 40% more likely to die of the disease than white women even though they’re given the same therapies. Cell cycle dysregulation was one of the most prominent differences in somatic biology that they found in both the normal breast and tumor tissue.
As a female who trained under senior white men and battled sexism once she became an independent scientist, Haricharan has experienced a taste of the stress responses she believes might explain some of the disparities in cancer outcomes seen among more minoritized groups. Simply being pregnant comes with huge physiological changes that could contribute to cancer's development and progression but have—to date—been understudied.
Part of the reason demographic nuances have been overlooked is because many foundational biological studies about cell cycle regulation have been done on bacteria and single-celled organisms that lack the “complexity of experience” in terms of aging, chronic stress, and gender, says Haricharan. In the case of breast cancer, another contributing factor is that many of the clinicians diagnosing women with breast cancer fail to consider their patients’ reproductive history, including when they had their first child and how recently they were pregnant. “It doesn’t come up.”
The reality is that breast tissue changes throughout much of a woman’s lifetime, including pregnancy and breastfeeding as well as during different stages of her menstrual cycle, Haricharan says. All these complex processes, while normal and natural, are also “cataclysmic” for the breast in terms of the microscopic changes happening in the cells. These truths would be less evident to men who represent the bulk of scientists in the cancer research field, she adds.
How much all these cell cycle differences occur because of age rather than fluctuating hormone levels needs to be more closely examined, says Haricharan. It wasn’t possible in the latest study to tease out age- and hormone-related differences using patient data because all the older women were post-menopausal, and all the younger women were pre-menopausal. When the question was studied in mice with less complex menstrual cycles, the breast cells of the animals chemically induced into premature menopause behaved much like those of their post-menopausal counterparts, but they didn’t fully capture the phenotype seen in the older women.
For the remainder of this year, Haricharan and her team will be conducting an experiment with mice in hopes of figuring out how much age is responsible for the cell cycle differences they have observed. The idea here is to look at the same mouse in its prime and as a senior citizen and compare how its breast cells deal with insults and how much of that response is prompted by changes to the immune system and accumulating chronic stress that comes with age.
One of the intriguing possibilities here is to reclassify breast cancer based on cell cycle dysregulation to improve the diagnosis of patients. Women are currently being diagnosed based on data collected in the 1970s with their disease subtyped based on tests for estrogen and progesterone hormone receptors and HER2, but they might be more finely grouped by molecular events that rapidly emerging therapeutics can target, such as cell cycle dysregulation, Haricharan says.
ER+/HER2- breast cancer, one of the most common forms of the disease, is typically treated with hormonal therapies, but about 20% of tumors resist treatment from the very beginning, and up to 40% develop resistance over time. Patients with TNBC are generally treated in a non-targeted fashion with a lot of chemotherapy. But any of these patients whose tumors have specific cell cycle dysregulation events could potentially be candidates for inhibitors that work downstream of these disruptions, she notes.
A likely next step for the research team will be a retrospective analysis where breast cancer patients are reclassified based on cell cycle dysregulation to learn if this new category better predicts their response to standard care. “There is so much work being done now in the realm of cell cycle inhibitors and regulators as targeted therapeutic options for cancer patients,” says Haricharan, making this an ideal time to dovetail that therapeutic approach with the reclassification exercise.
Haricharan and her colleagues are now working with the drug discovery core at Sanford Burnham Prebys to explore the possibility of developing a targeted small molecule that would reactivate regulators shut down by cancer to “reawaken” tight, pre-menopausal cell cycle regulation. As she knows from talking with chemists, this would be no easy task, which is why most current therapeutics are inhibitory.
“The rewards of developing such therapeutics... certainly justify this high-risk approach,” Haricharan is quick to add. Cancer needs to be studied in the context of unique host characteristics that help drive how cancer cells transform and grow.