A newly published paper in Cell Reports journal, entitled “Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity,” reported new insights into the reasons why many women with estrogen receptor-positive (ER+) breast cancer form resistance to hormone treatment, and suggests an approach to effective treatment for them.
Breast cancer is a common form of cancer in women, often developing after the age of 50. Common risk factors include genetic predisposition, use of birth control therapy, cigarette smoking, and diverse polluting particles.
From a mechanistic point of view, it is well-documented that breast cancers require estrogen to grow. The latter binds to two types of hormone receptors: estrogen receptors (ER+) and progesterone receptors (PR+). Nearly 80% of breast cancers are classified as ER+. They are treated using anti-oestrogen drugs that either block the receptors, like tamoxifen, or block the production of estrogen aromatase inhibitors, like anastrozole and letrozole.
In around one in five of ER+ cases, the cancer is known to recur within 10 years, and most advanced breast cancers develop resistance to therapy. With this in mind, the research team performed a series of in vitro studies and in vivo studies involving patient-derived breast cancers in mice.
The results showed that treatment with anti-oestrogen drugs for short periods reduced tumor growth, but it enhanced activity of stem cells directed by a protein named NOTCH4, which controls signaling within breast cancer cells. In mice models and cell cultures, it was confirmed that NOTCH4 prevented cancer stem cells from reacting with anti-oestrogen treatment, building up resistance to the drug. The presence of substantial levels of NOTCH4 in patients tumors prior to treatment also was associated with cancer spread and poorer survival rates.
The researchers treated the tumor stem cells with a substance that inhibits NOTCH4. The results showed that when compared to standard therapy using only the anti-oestrogen tamoxifen, therapy using tamoxifen in combination with a NOTCH4 inhibitor slowed the proliferation of breast cancer stem cells and tumor development.
Dr Rob Clarke, study team leader and a researcher with the Breast Cancer Now Research Unit at The University of Manchester’s Institute of Cancer Sciences, said in a university release: “This showed us that combining standard hormonal therapies with a NOTCH pathway inhibitor, or other drugs targeting breast cancer stem cells, could improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.”
Furthermore, evaluating the levels of NOTCH4 (or a similar molecule named ALDH1) present in stem cells could prove a way to predict which patients may develop resistance to anti-oestrogen treatment and which could benefit most from a combined anti-oestrogen therapy-NOTCH inhibitor treatment.
“Validating these findings will take time but general inhibitors of the NOTCH pathway are already being tested in breast cancer clinical trials. The development of resistance to cancer therapies is a huge challenge in the clinic which is why it’s vitally important that we continue to find ways to counteract it, taking us closer towards our ambitious goal of stopping women dying from this devastating disease by 2050,” the authors concluded.