Women's Hormones Linked to Ovarian and Breast Cancers
Hormones have a lot of influence and travel everywhere in your body. They are the chemicals that tell your body, right down to the cells, what to do. Things like defining how big you will grow, how you process food, to how your immune system works. Hormones can touch your weight, your body temperature, even your mood. On a scientific level, hormones are the molecules in your body that are created and released by the glands of your endocrine system. The system that controls, produces, and communicates to your hormones with the rest of the body. Unfortunately, they may also play a big part with regards to cancer risk. Dr. Carol Lange at the University of Minnesota in the Department of Medicine is working to discover just what the relationship is between hormones and cancer? It has a lot to do with cells multiplying.
Breast cancer (BC) is responsible for approximately15% of cancer-related death in American women. The breast is created by a system of lobes and branching tubes that exit at the nipple and BC develops in the tissues that makes up this system. It takes on many different forms, each with different behavior and treatments. The major effects of hormones on the breast occur at puberty and during pregnancy and lactation. Today, we no longer see breast cancer as a single disease, now we know that it’s a group of separate conditions. If you are facing BC, it is important to get an accurate diagnosis that will define the right treatment for your specific condition.
In general, cancer develops after the genetic material in cells changes and the cells grow out of control. When there are enough of these abnormal cells, they form a tumor that is visible on a mammogram or felt as a lump during a breast exam. Not all tumors in the breast are cancerous. A biopsy can help your doctor evaluate a tumor that looks suspicious.
Many patients wonder why they developed breast cancer or if they are at a high risk for the disease. Most breast cancers result from the accumulation of random mutations, or mistakes, in genes. Because these mutations increase over time, your risk of developing cancer also increases as you get older. About 5% to 10% of breast cancers are linked to inherited genetic mutations in genes such as BRCA1 and BRCA2. These “loss-of-function” mutations make it difficult for cells to fix the random mutations in DNA that occur over time. Patients who have an inherited mutation in either BRCA1 or BRCA2 are at a much higher risk of developing breast cancer, often at a younger age than the average woman.
There is no sure way to prevent breast cancer. Some risk factors can be controlled to help reduce risk. People at high risk may want to take certain medicines or even have surgery to remove their breasts to prevent breast cancer. Regular testing to look for breast cancer is the best way to find it when it’s small and before it has spread. A mammogram can show BC before tumors are big enough to feel or cause problems. People at high risk may get another test, called an MRI, along with their mammograms. If you find a lump, you should see a healthcare provider right away. The healthcare provider will look at your breasts and feel the lump. Ultrasound may be used to see if the lump is solid or filled with fluid. A biopsy is the only way to know if a lump or change is cancer. Small pieces of tissue (biopsies) are taken out and checked for cancer cells. A hollow needle may be used to take out suspicious bits of tissue. The samples are sent to a lab and your results will come back in about 1 week.
After a diagnosis of breast cancer, you may have other tests. These help your healthcare providers learn more about the cancer. They can help determine the stage of the cancer. The stage is how much and how far the cancer has spread (metastasized) in your body. It is one of the most important things to know when deciding how to treat the cancer.
The primary method of classifying breast cancer relies on the presence or absence of estrogen receptor (ER), the ER target gene progesterone receptor (PR), and amplification of the human epidermal growth factor receptor 2 (HER2). These molecular markers in part dictate the treatment regimen that BC patients receive. When these receptors are present, targeted therapies are used to decrease recurrence rate and improve survival (e.g., tamoxifen inhibits ER and trastuzumab/pertuzumab targets HER2). However, triple-negative breast cancers (TNBC), which account for 15% to 20% of all breast cancer patients, lack these receptors and are thus defined by this feature. Although TNBC is intensely studied, molecular targeted therapies are still largely unavailable for TNBC patients, who suffer from higher disease recurrence, more frequent metastasis, and a worse prognosis relative to patients with other BC subtypes. Thus, appropriate biomarkers of driver pathways and new therapeutic targets are urgently needed. Dr. Lange and colleagues recently published an article in Endocrinology July 2023 Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4 highlighting how tailored therapies that target genes (such as PDK4) induced by glucocorticoids (including the hormone cortisol) that are needed for cancer metabolism could greatly improve TNBC patient survival.
Ovarian cancer (OC) is the sixth most common tumor in women. It is the most common malignancy after breast cancer in women over 40 years of age, particularly in developed countries. Alterations for OC are transmitted through mitosis from one cell to another, but are not transmitted from parents to children. More than 200,000 new cases are diagnosed each year worldwide. Each year, it constitutes 3.4% of all cancers diagnosed in women, and there are 6.6 new cases per 100,000 women per year. OC is generally considered to be a postmenopausal disease, since the reported median age at diagnosis is 63 years. Its history has been known scientifically for over 150 years. During this time, its mortality rate has not changed but its incidence has. The former despite treatments, which are highly expensive and sophisticated.
While the five-year survival rate has steadily increased from 30–50% with the use of cisplatin, in total, there is only a 5% increase, from 20% to only 25%, in women with advanced tumors. The poor survival rate is related to the diagnosis made in the advanced stages of the disease. It is a neoplasm that responds well to systemic chemotherapy in more than 80% of the cases, when it is administered together with optimal cytoreductive surgery. Despite complete remission (CR) with first-line chemotherapy (CT), ovarian epithelial cancer recurs in over 50% of women.
OC represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal symptoms contributes to high fatality rates. With the exception of BRCA1 and BRCA2 mutation carriers, OC most often manifests as a post-menopausal disease, a time in which the ovaries regress and circulating reproductive hormones diminish. Progesterone is thought to be a “protective” hormone that counters the proliferative actions of estrogen, as can be observed in the uterus or breast. Like other steroid hormone receptor family members, the transcriptional activity of the nuclear progesterone receptor (nPR) may be ligand dependent or independent and is fully integrated with other ubiquitous cell signaling pathways often altered in cancers. Emerging evidence in OC models challenges the singular protective role of progesterone/nPR.
Dr. Lange and colleagues have recently published an article in Endocrine Reviews June 2023, Reevaluating the Role of Progesterone in Ovarian Cancer: Is Progesterone Always Protective? Looking into the historical perspective of progesterone on OC development and progression with exciting new research findings and critical interpretations to help paint a broader picture of the role of progesterone and nPR signaling in OC. Dr. Lange hopes to alleviate some of the controversy around the role of progesterone and shed some light into the importance of nPR actions in disease progression. A new perspective on the role of progesterone and nPR signaling integration will raise awareness to the complexity of nPRs and nPR-driven gene regulation in OC, helping to reveal novel biomarkers, and lend critical knowledge for the development of better therapeutic strategies.
Progesterone was traditionally perceived as a protective factor for epithelial OC since hormonal contraceptive use and certain reproductive states such as pregnancy correlate with lower cancer risk in premenopausal women. High-grade serous ovarian cancer (HGSOC), an aggressive subtype of OC, is often considered a postmenopausal disease because diagnosis typically occurs during this stage of reproductive senescence. We now know that precursor lesions develop much earlier, during a time when ovarian steroid hormones like estrogen and progesterone are prevalent, and that these steroids play significant roles in disease initiation and progression.
The hormonal milieu is much more complex than progesterone alone. Precursor fallopian tube lesions and advanced tumors synthesize and secrete progesterone and estrogen, express their receptors and those of other steroids (eg. androgens, glucocorticoids), and exhibit active steroid receptor signaling, suggesting the importance of a steroid-rich microenvironment. An accurate understanding of progesterone's role in disease progression will require an appreciation of the complexity of nPRs and nPR-driven gene regulation and the further exploration of their interplay with other steroid hormone receptors and DNA damage signaling pathways. Dr. Lange is exploring the rolw of BRCA1 and BRCA 2 deficiency associated with dysfunctional elevated nPR signaling that together may promote increased DNA damage. Exploring these facets of progesterone action should help clarify the ultimate role of this hormone as anti-tumorigenic or pro-tumorigenic during the evolution of the collection of diseases grouped together as OC.
Carol Lange, PhD is a Professor of Medicine in Division of Hematology, Oncology, and Transplantation and the Associate Director for Basic Science at the University of Minnesota Masonic Cancer Center. Her research is focused on the role of steroid hormone receptors (SRs) in breast and ovarian cancer. Estrogen receptors (ER) and progesterone receptors (PR) are context-dependent transcription factors that are important for normal breast development during puberty and pregnancy. Dr. Lange has over 30 years of experience in mechanisms of signal transduction related to cancer biology and altered cell fate, and the regulation of proteins by post-translational modifications. She has routinely developed new reagents (antibodies, stable cell lines, mouse models) and employed biochemistry and modern cell and molecular biology techniques as well as NextGen approaches to study the mechanisms of hormone action and altered gene regulation related to cancer biology and tumor progression. As a leading scientist focused on hormones and cancer, and in her leadership roles as Director of the Cancer Biology Training (NIH T32) Program and Associate Director for Basic Science within the Masonic Cancer Center, she has mentored over 30 PhD and postdoctoral trainees as well as numerous junior faculty members.
Dean Patterson, Editor
Division of Hematology, Oncology, and Transplantation
References:
Dwyer AR, Perez Kerkvliet C, Truong TH, Hagen KM, Krutilina RI, Parke DN, Oakley RH, Liddle C, Cidlowski JA, Seagroves TN, Lange CA. Glucocorticoid Receptors Drive Breast Cancer Cell Migration and Metabolic Reprogramming via PDK4. Endocrinology. 2023 Jun 6;164(7):bqad083. doi: 10.1210/endocr/bqad083. Erratum in: Endocrinology. 2023 Jun 26;164(8): PMID: 37224504; PMCID: PMC10251300.
Mauro LJ, Spartz A, Austin JR, Lange CA. Re-evaluating the role of progesterone in ovarian cancer: is progesterone always protective? Endocr Rev. 2023 Jun 1:bnad018. doi: 10.1210/endrev/bnad018. Epub ahead of print. PMID: 37261958.
Basic Information about Ovarian Cancer
https://www.cdc.gov/cancer/ovarian/basic_info/index.htm
What is Breast Cancer? https://www.cdc.gov/cancer/breast/basic_info/what-is-breast-cancer.htm
