This article is more than 5 years old. Information may no longer be current.
Nuclear receptors play key role in hormone-dependent malignancies
Click Here to Manage Email Alerts
NEW ORLEANS — Most women and men with hormone receptor-positive breast or prostate cancers eventually become resistant to targeted endocrine therapies, and several key mechanisms likely play a role in that resistance, according to a speaker at the Endocrine Society annual meeting.
“Estrogen receptor is a key lineage determining transcription factor in the breast required for normal mammary gland development, and it is also essential for the growth of more than two-thirds of breast cancers,” Myles Brown, MD, director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute, and the Emil Frei III professor of medicine at Harvard Medical School, told Endocrine Today before his presidential plenary presentation. “Despite effective therapies to lower estrogen levels or block estrogen receptor action, most women with advanced estrogen receptor-positive breast cancer will become resistant to these endocrine therapies.”
Brown’s lab has focused on a key question, he said: Why is it that breast and prostate cancers depend exclusively on the action of reproductive steroid hormones?
“We’ve come to the idea that what determines the sensitivity and dependence on these steroid hormones is actually a reflection of the lineage that these tumors arise from — that normal development of the tissues depends on these steroid hormones,” Brown said during his presentation. “Then we asked: What is it that determines whether a tumor can become resistant to the action of drugs that either reduce hormone levels or block receptors directly? As is the case for all targeted therapies, there are several standard answers.”
Negative feedback
Brown highlighted two important mechanisms of tumor resistance: one involving mutations in estrogen receptor itself, and the other caused by a hard-wired feedback loop that limits the efficacy of endocrine therapies targeting estrogen receptor, including tamoxifen, aromatase inhibitors and antiestrogens.
“As in endocrinology quite often, systems have feedback loops to maintain homeostasis, and perhaps one or more of these feedback loops is limiting the efficacy of our current therapies that attempt to completely limit the activity of the steroid receptor,” Brown said.
Aromatase inhibitors have been effective in the treatment of hormone receptor-positive breast cancer; however, in the advanced-disease setting, almost all of these women will experience relapse, Brown said. Upon relapse, many women have mutations in the estrogen receptor that allow it to act in the absence of a steroid hormone.
Research has demonstrated that the estrogen receptor gains another disadvantageous phenotype — in addition to turning on programs important for estrogen-stimulating growth, they also turn on a set a genes for promoting metastases.
“This leads to the idea that this metastatic phenotype of cancer might be an epiphenomenon,” Brown said. “One-third of women who become resistant to endocrine therapy in the advanced-disease setting have one or more of the activating estrogen receptor mutations, and [the mutations] may not only make the tumors grow in the absence of estrogen, but they may play a role in promoting metastatic spread.”
Brown said researchers may have missed the possibility that endocrine therapies are limited by the existence of such feedback loops.
“One of the problems we have with using endocrine therapy alone in estrogen receptor-positive breast cancer is that hitting this pathway once is not enough when you have feedback,” Brown said. “Targeting one of the oncogenic pathways together with [estrogen receptor] increases the efficacy of current endocrine therapies.”
Genetic clues
Similarly, in the prostate, androgens and androgen receptor are required for normal development, whereas most prostate cancers also depend on androgen receptor for growth, Brown said.
“As in breast cancer endocrine therapy, most men with advanced prostate cancer eventually become resistant to androgen receptor-targeted therapies,” Brown said in an interview before the presentation.
Brown highlighted the importance of the expression of androgen receptor splice variants and, in particular, a variant known as AR-v7, in supporting the growth of castration-resistant prostate cancer.
Research suggests that four key genes are directly repressed by AR-v7 and could potentially predict poor outcomes in men with prostate cancer, Brown said. In studies where men with prostate cancer were stratified by low, middle and high levels of expression of these four genes, as a reflection of increased AR-v7 activity, researchers observed a unique phenomenon.
“We found that men with high levels — that is, maintaining expression of these four tumor suppressor genes — had much better outcomes than the men with low- or middle-level expression,” Brown said. “This confirms the idea that the genes that we found in the AR-v7 represented in the model system may be important clinically.” – by Regina Schaffer
Reference:
Brown M. Nuclear receptor signaling in breast and prostate cancer. Presented at: The Endocrine Society Annual Meeting; March 23-26, 2019; New Orleans.
Disclosure: Brown reports he has received sponsored research support from Novartis, serves on an advisory board for Kronos Bio and has served as a consultant for GTx Inc.