Additional File : Supplementary Figure S3
Histological analysis of excised long bones in the Y537S ER mutant model. An example of H& E staining of bone marrow for a vehicle-treated mouse. Insert shows bone metastases stained with anti-luciferase antibody and H& E staining . An example of H& E staining of bone marrow for a 5mg/kg lasofoxifene-treated mouse. No metastases were observed. Description of data: The figure shows examples of H& E and IHC staining images of bone marrow after treatment with vehicle and lasofoxifene.
What Is The Treatment For Hormone Receptor Negative Breast Cancer
Treating Hormone Receptor-Negative Breast Cancer Surgery is the primary treatment option for most cases of hormone receptor-negative breast cancer. Lumpectomy removes the tumor and some surrounding normal tissue. Radiation therapy is usually necessary afterwards. Mastectomy removes the entire breast.
Hormone Receptor Positive Breast Cancer
Your breast cancer may be hormone receptor-positive or HR+. Some breast cancers have receptors on them that attach to the hormones, estrogen, and progesterone, as they circulate in your body. These hormones feed the cell and help it grow.
- If your tumor has hormone receptors, it is called hormone receptor-positive or HR+. If your tumor is HR+, the tumor needs estrogen and/or progesterone to grow.
- About 80% of breast cancers are HR+.
- If your tumor does not have hormone receptors, it is hormone receptor-negative or HR-.
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If Cancer Comes Back Or Has Spread
AIs, tamoxifen, and fulvestrant can be used to treat more advanced hormone-positive breast cancers, especially in post-menopausal women. They are often continued for as long as they are helpful. Pre-menopausal women might be offered tamoxifen alone or an AI in combination with an LHRH agonist for advanced disease.
Colony Formation And Cell Proliferation Assays
For the colony formation assay, wild-type MCF-7 cells, intermittent hypoxic cells, MCF-7/HIF-1 and MCF-7/vector cells were seeded into six-well plates and treated with fulvestrant with or without zoledronic acid . Medium was replaced every 3 to 4 days. After 11 days, adherent cells were fixed in 10% formaldehyde for 20 min and then stained with 0.1% crystal violet for 30 min. The surviving colonies consisting of 50 or more cells were counted.
Cell proliferation assays were performed using a Cell Counting Kit-8 according to the manufacturer’s instructions. Briefly, MCF-7/vector and MCF-7/HIF-1 cells were seeded in 96-well plates and were treated with fulvestrant and zoledronic acid for different periods of time . CCK-8 solutions were added to each well, and the plates were incubated for 3 h at 37°C. Absorbance was measured at 450 nm with a microplate reader and normalized to the value of untreated cells. A duplicate plate of untreated cells was measured at 24 h.
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Other Factors And Proteins
There are several other transcription factors and proteins that determine cancer progression in the face of ongoing endocrine therapies, some known and many unknown. The EMT factors, Twist and Snail, have been implicated in endocrine resistance, with Twist downregulating ER by epigenetically regulating the promoter of ER . There are several other proteins and molecules that play a major role in endocrine resistance, including the NOTCH and WNT pathways described earlier. All these proteins and transcription factors function as individual molecules working together for/against the homeostasis of the human cells, to determine the fate of cancer cells.
Metabolic and oxidative stress are a few of the other factors affecting endocrine resistance. The mechanisms are elucidated in detail below for each of these factors. Recent publications have demonstrated that homeostasis in cell metabolism and cell proliferation is mediated by a few other transcription factors and pathways as well. Another mechanism for endocrine resistance that has been suggested relates to the ability of the metabolic enzymes to deliver the active compound. Some studies have reported lower concentrations of BC drugs at the site of the tumor when compared to levels in the plasma and an association with poor outcomes . Alternatively, a recent study demonstrated that an elevated concentration of tamoxifen metabolites at the site of the cancer, led to agonist effects .
When Breast Cancer Spreads
Breast cancer can spread to other parts of the body through blood or lymph, which is the fluid of the lymphatic system. Common sites of spread, or metastasis, include the bones, brain, liver, and lungs, according to the American Society of Clinical Oncology .
Breast cancer can be metastatic when first diagnosed. In most cases, however, it spreads later, after treatment for non-metastatic disease, and the reason is unclear. The cancers stage, speed of growth, and hormone receptor status influence whether it spreads, ASCO reports.
Certain factors can increase your risk of developing breast cancer, regardless of whether its metastatic or non-metastatic. These risk factors include:
- Being older than 50
- Family history of breast cancer or
- Getting pregnant for the first time after 30
- Having had breast cancer or ovarian cancer
- Hormone replacement therapy, which is different from hormone therapy for cancer, to treat post-menopause symptoms
- Inherited genetic changes, such as mutations in the BRCA1 or BRCA2 genes
- Low levels of physical activity
- Reaching menopause after 55
- Starting menstruation before 11
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How Can Hormone Receptors Be Used To Slow Cancer Growth
Blocking the action of estrogen and/or progesterone could possibly stop the cancer from growing. There are a few ways in which this can happen:
- Blocking the hormone receptor with another compound prevents the estrogen or progesterone from being able to attach to the receptor and activate the cell.
- Prevent the body from making the hormone: This can be done with medication to block the production of the hormone, or with surgery to remove the organ that makes it. For example, estrogen production can be significantly decreased by surgically removing the ovaries.
- Eliminate the hormone receptors on cells or change their shape: This makes it impossible for the hormone to attach itself to the cell receptor and to activate it, essentially making the hormone unable to function.
Why Is Knowing Hormone Receptor Status Important
Knowing the hormone receptor status of your cancer helps doctors decide how to treat it. If your cancer has one or both of these hormone receptors, hormone therapy drugs can be used to either lower estrogen levels or stop estrogen from acting on breast cancer cells. This kind of treatment is helpful for hormone receptor-positive breast cancers, but it doesnt work on tumors that are hormone receptor-negative .
All invasive breast cancers should be tested for both of these hormone receptors either on the biopsy sample or when the tumor is removed with surgery. About 3 of 4 breast cancers have at least one of these receptors. This percentage is higher in older women than in younger women. DCIS should also be checked for hormone receptors.
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If You Cant Have Surgery
Surgery is the main treatment for breast cancer, but some women have health problems that mean they cant have surgery. Some women choose not to have surgery.
In this case, if your breast cancer is oestrogen receptor positive, your doctor might recommend hormone therapy. This treatment won’t get rid of the cancer but can stop it growing or shrink it.
The treatment can often control the cancer for some time. Your doctor might change you to a different type of hormone treatment if your cancer starts growing again.
What Hormones Are Used To Block The Growth Of Breast Cancer Cells
The cells of this type of breast cancer have receptors that allow them to use the hormone estrogen to grow. Treatment with anti-estrogen hormone therapy can block the growth of the cancer cells. Progesterone receptor positive. This type of breast cancer is sensitive to progesterone, and the cells have receptors
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What Is A Hormone Receptor
Hormones are chemical messengers that circulate in the bloodstream. Hormone receptors are proteins located in and around breast cells. When the corresponding hormone binds to a receptor, it tells the cells how to grow and divide.
In the case of breast cancer, these receptors allow abnormal cells to grow out of control, which results in a tumor.
Adjuvant Hormonal Therapy Treatment Time
For many years, women took hormonal therapy for five years after surgery for early-stage, hormone receptor-positive breast cancer. In most cases, the standard of care is five years of tamoxifen, or two to three years of tamoxifen followed by two to three years of an aromatase inhibitor, depending on menopausal status.
Recent research has found that in certain cases, taking tamoxifen for 10 years instead of five years after surgery lowered a womans risk of recurrence and improved survival.
In most cases, a post-menopausal woman diagnosed with early-stage, hormone receptor-positive breast cancer would take an aromatase inhibitor for five years after surgery to reduce the risk of recurrence. After that, if breast cancer had been found in the lymph nodes, called node-positive disease, a woman would take an aromatase inhibitor for an additional five years, for a total of 10 years of hormonal therapy treatment.
Doctors call taking hormonal therapy for 10 years after surgery extended adjuvant hormonal therapy.
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Estrogen Receptor And Signaling
ER is a nuclear receptor and belongs to the steroid-thyroid-retinoid receptor superfamily . The human ER is comprised of two subdivisions: ER and ER, located on chromosomes 6 and 14 at 6q21.5 and 14q23.2, respectively . In some tissues, like the uterus, mammary gland, testis, pituitary, liver, kidney, heart, and skeletal muscle, ER appears to dominate, whereas in the ovary and prostate, ER is highly expressed. The role of ER in breast malignancy is well-documented, while the function of ER remains ambiguous . It is understood that ER has contrasting effects to ER, and inhibits the stimulatory effects of E2 on cell proliferation. Studies have shown that downregulation of ER contributes to tumor progression and the chances of survival increase with an increase in the expression of ER .
Figure 2. Schematic figure of the structure of ER and ER. The AF1 site is located at the N-terminus A/B domain. The DBD and dimerization site is present within the C domain. The nuclear localization signal is contained in the D domain. The E/F domain contains the AF2 site as well as the ligand binding domain along with a dimerization site. Notable mutations within ER are depicted for the ER gene.
Table 1. Post-translational modifications in ER.
What Are Hormones And Hormone Receptors
Hormones are substances that function as chemical messengers in the body. They affect the actions of cells and tissues at various locations in the body, often reaching their targets through the bloodstream.
The hormones estrogen and progesterone are produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women and in men. Estrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.
Estrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors that become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes, which can stimulate cell growth.
Breast cancers that lack ERs are called ER negative, and if they lack both ER and PR they may be called HR negative.
Approximately 67%80% of breast cancers in women are ER positive . Approximately 90% of breast cancers in men are ER positive and approximately 80% are PR positive .
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D Combination Of Cdk4/6 With Pi3k/akt/mtor
The remarkable results observed with CDK4/6 inhibitors has been very well-received and approved by the FDA. However, a large number of ER+ BC patients continue to experience relapse and recurrence . There is a complex crosstalk between ER+ BC, constitutive PI3K activation and the CDK4/6 pathway. This provides a strong rationale for the combined targeting of both the CDK4/6 and PI3K pathways in effective control of the tumor progression . Studies have suggested that inhibition of the either the CDK4/6 or the PI3K/AKT pathway, delays the onset of endocrine resistance . Combinatorial inhibition of both the PI3K and CDK4/6 pathways overcomes the resistance due to single agent inhibition by CDK4/6 by downregulating cyclin D1 and arresting cell cycle progression . Several combination therapy trials are underway to identify the best strategy to overcome endocrine resistance in ER+ BC. Trials that combine the CDK4/6 inhibitors with various PI3K/AKT/mTOR inhibitors are ongoing, with the aim to inhibit tumor growth and prevent relapse. The triplet inhibitor trial with ribociclib, fulvestrant and BKM 120 or BYL719 in HR+/HER2-negative advanced or MBC is one study aimed to study its efficacy and suitability as a mode of treatment in these patients.
Possible Side Effects Of Ais
The most common side effects of AIs are:
- Bone and joint pain
AIs tend to have side effects different from tamoxifen. They don’t cause uterine cancers and very rarely cause blood clots. They can, however, cause muscle pain and joint stiffness and/or pain. The joint pain may be similar to a feeling of having arthritis in many different joints at one time. Options for treating this side effect include, stopping the AI and then switching to a different AI, taking a medicine called duloxetine , or routine exercise with nonsteroidal anti-inflammatory drugs . But the muscle and joint pain has led some women to stop treatment. If this happens, most doctors recommend using tamoxifen to complete 5 to 10 years of hormone treatment.
Because AIs drastically lower the estrogen level in women after menopause, they can also cause bone thinning, sometimes leading to osteoporosis and even fractures. If you are taking an AI, your bone density may be tested regularly and you may also be given bisphosphonates or denosumab , to strengthen your bones.
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What Do The Hormone Receptor Test Results Mean
Test results will give you your hormone receptor status. It will say a tumor is hormone receptor-positive if at least 1% of the cells tested have estrogen and/or progesterone receptors. Otherwise, the test will say the tumor is hormone receptor-negative.
Hormone receptor-positive breast cancer cells have either estrogen or progesterone receptors or both. These breast cancers can be treated with hormone therapy drugs that lower estrogen levels or block estrogen receptors. Hormone receptor-positive cancers tend to grow more slowly than those that are hormone receptor-negative. Women with hormone receptor-positive cancers tend to have a better outlook in the short-term, but these cancers can sometimes come back many years after treatment.
Hormone receptor-negative breast cancers have no estrogen or progesterone receptors. Treatment with hormone therapy drugs is not helpful for these cancers. These cancers tend to grow faster than hormone receptor-positive cancers. If they come back after treatment, its often in the first few years. Hormone receptor-negative cancers are more common in women who have not yet gone through menopause.
Triple-positive cancers are ER-positive, PR-positive, and HER2-positive. These cancers can be treated with hormone drugs as well as drugs that target HER2.
Three Aromatase Inhibitors Are Approved For Use By The Us Food And Drug Administration : Anastrozole Letrozole And Exemestane
All three aromatase inhibitors have known side effects. The most common is bone and joint pain. Other side effects women report include fatigue, dizziness, hot flashes, and weight gain. All of these side effects can affect your quality of life, and you may be able to tolerate some more than others. If you find the side effects are keeping you from taking the hormone therapy that you were prescribed, you can talk to your doctor about switching to one of the other aromatase inhibitors. You can also discuss switching to tamoxifen.
In June 2014, ASCO updated its hormone treatment guidelines. The new guidelines incorporate new research findings, including a large study that found that 10 years of tamoxifen was more effective than five years of tamoxifen followed by a placebo.
The new treatment guidelines for women with hormone-sensitive breast cancer are:
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Estrogen And Progesterone Receptor Testing For Breast Cancer
To help doctors give their patients the best possible care, the American Society of Clinical Oncology and the College of American Pathologists developed evidence-based guidelines to improve the accuracy of testing for estrogen and progesterone receptors for breast cancer. This guide for patients is based on ASCO’s and CAP’s 2020 updated recommendations.
How Much Lower Risk Of Dying From Breast Cancer
People diagnosed with breast cancer that was estrogen-receptor-positive and progesterone-receptor-positive had a 30% to 60% lower risk of dying from breast cancer compared to people diagnosed with breast cancer that was positive for only one hormone receptor. For people diagnosed with breast cancer that was positive for only one hormone receptor,
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What Does It Mean When A Breast Cancer Is Her2 Negative
When a breast cancer is HER2-negative, it means that the cancerous cells do not contain high levels of the protein HER2. There are many treatment options available for this type of breast cancer, but the prognosis can vary. HER2 stands for human epidermal growth factor receptor 2. The term HER2 may refer to the HER2 gene or to the protein HER2,
What Are Estrogen And Progesterone Receptors
Receptors are proteins in or on cells that can attach to certain substances in the blood. Normal breast cells and some breast cancer cells have receptors that attach to the hormones estrogen and progesterone, and need these hormones for the cells to grow.
Breast cancer cells may have one, both, or none of these receptors.
- ER-positive: Breast cancers that have estrogen receptors are called ER-positive cancers.
- PR-positive: Breast cancers with progesterone receptors are called PR-positive cancers.
- Hormone receptor-positive: If the cancer cell has one or both of the receptors above, the term hormone-receptive positive breast cancer may be used.
- Hormone receptor-negative: If the cancer cell does not have the estrogen or the progesterone receptor, it’s called hormone-receptor negative .
Keeping the hormones estrogen and progesterone from attaching to the receptors can help keep the cancer from growing and spreading. There are drugs that can be used to do this.
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