Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women

BACKGROUND: The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer. METHODS: We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires. RESULTS: Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use. CONCLUSION: Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.     

Progesterone regulation of stem and progenitor cells in normal and malignant breast

Progesterone plays an important, if not controversial, role in mammary epithelial cell proliferation and differentiation. Evidence supports that progesterone promotes rodent mammary carcinogenesis under some conditions, progesterone receptors (PR) are necessary for murine mammary gland tumorigenesis, and exogenous progestin use in post-menopausal women increases breast cancer risk. Thus, the progesterone/PR signaling axis can promote mammary tumorigenesis, albeit in a context-dependent manner. A mechanistic basis for the tumor promoting actions of progesterone has thus far remained unknown. Recent studies, however, have identified a novel role for progesterone in controlling the number and function of stem and progenitor cell populations in the normal human and mouse mammary glands, and in human breast cancers. These discoveries promise to reshape our perception of progesterone function in the mammary gland, and have spawned new hypotheses for how progestins may increase the risk of breast cancer. Here we review studies on progesterone regulation of mammary stem cells in normal and malignant tissue, and their implications for breast cancer risk, tumorigenesis, and tumor behavior.     

The biology of progesterone receptor in the normal mammary gland and in breast cancer

This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.     

Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects

Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of progestin-induced VEGF by the antiprogestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to progestins, suggests that these effects are mediated by amplification of the progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.     

Comparative analysis of the uterine and mammary gland effects of drospirenone and medroxyprogesterone acetate

The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA), compared with conjugated equine estrogens-only treatment. These findings continue to be discussed, and it remains to be clarified whether the results obtained for MPA in the Women's Health Initiative study are directly applicable to other progestins used in hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA, and drospirenone in two major target organs: the uterus and mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal side branching in the mammary gland, and proliferation of mammary and uterine epithelial cells as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the natural hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.     

The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?

Considerable animal research and clinical trials demonstrate that progesterone antagonists could treat hormone-dependent breast cancers. Since endogenous progesterone does include mitosis in epithelial cells of the breast, in theory, exogenous progesterone can cause breast cancer. Thus administration of progesterone antagonists could block endogenous progesterone. Yet we do not know the mitosis pattern in breast cancer cells during the menstrual cycle, so research obtaining such data is needed. Ethical problems arise, however, since researchers need multiple breast tumor samples to analyze proliferative activity at various times during the cycle. A possible solution is using an aspirated tumor sample for initial mitotic analysis immediately followed by RU-486 treatment then tumor removal 24 hours later for reanalysis. Ideally well controlled studies using organ-cultured human breast tumors, human breast cancer lines, and human tumors implanted into nude mice are needed to understand the mechanisms of the mitogenic actions of progestins and progestin antagonists. Progestin antagonist may be used to treat locally advanced or metastatic cancers either as an adjuvant endocrine therapy alone or with tamoxifen. An obstacle to longterm use of RU-486 as a treatment for breast cancer is its antiglucocorticoid side effects. But the molecules of newer progesterone antagonists appear to produce maximal antiprogestin activity and minimal antiglucocorticoid activity. In addition, if RU-486 is administered with drugs that prevent adrenal steroidogenesis or peripheral aromatization of adrenal steroids to estrogens, women may take it for longterm treatment. Researchers must have the opportunity to continue basic tumor biological and molecular research to gain an understanding of the exact molecular targets and mechanisms of antagonist action. The current political climate in the US hinders such research, however.     

Sex hormones and cardiovascular risk

The metabolic effects of sex steroids pertinent to cardiovascular risk are described. These effects are discussed for estrogen inducible proteins, coagulation and fibrinolysis, blood pressure and hypertension, carbohydrate metabolism, lipids and lipoproteins, and vessel walls and local prostaglandins. Also described is the cardioprotection from estrogens and estrogen/progesterone treatment and cardiovascular risk. Oral contraceptive (OC) and cardiovascular risk are also discussed with the following effects identified: the influence on many of the multiple risk factors involved in the development of cardiovascular diseases (i.e., lipids, carbohydrate metabolism, and hemostasis), an association between OC use and thromboembolic accidents, a state of hypercoagulability counterbalanced by increased fibrinolytic activity, venous thrombosis, a relationship with the dosage of androgenic progestogens. no atherogenic origin, no age limit for prescribed, healthy, nonsmoking women, and an increased peripheral insulin resistance. It is concluded that it is rarely inadvisable to prescribe low dose natural estrogens in postmenopausal hormone replacement therapy. Factors contraindicating such use are undiagnosed genital bleeding, an active thrombolic or cardiovascular process, carcinoma of the breast or endometrium, and acute liver failure. Estrogen replacement therapy may exert some cardioprotective effect. When progestogens are added to prevent endometrial carcinoma development, the benefits might be reduced. Low estrogen and low progesterone OC use among healthy, nonsmoking women even in middle age poses no risk of death from cardiovascular disease. Premenopausal women may even be protected from coronary atherosclerosis with estrogen-containing OCs. However, it is advisable that OCs be used with the least possible impact on lipid and carbohydrate metabolism, as well as on hemostasis. For those with some prior cardiovascular risk, there are theoretical advantages at present for use of the new, less, or nonandrogenic progestins in OCs; however, caution is urged and informed consent must be obtained until epidemiological studies support this position.     

Interplay between progesterone and prolactin in mammary development and implications for breast cancer

Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer.     

Breast cancer and post-menopausal hormone therapy

From the introduction of post-menopausal hormone replacement therapy (HRT) there has been great concern that HRT could possibly increase the risk of breast cancer. Prolonged exposure to endogenous oestrogens undeniably increases the risk of breast cancer. Questions that are important and until now only partly answered, are the following. Are oestrogens tumour promoters, as they induce mitosis, lead to proliferation and, therefore, accelerated growth of clinically occult pre-existing tumours? In addition to this, are they genotoxic mutagenic carcinogens, or could they initiate tumours by way of accumulation of incessant DNA-replication damage mechanism? Opinions vary as to the effect of the addition of a progestogen. There is a multitude of different progestogens which could bind with differing affinity to progesterone receptor PR-A or PR-B, and which have different physiological functions via differential gene regulation. The action of a progestogen on the oestrogen-induced cellular mitotic activity could be synergistic or antagonistic (by different pathways: oestrogen receptor downregulation, activating of metabolic pathways within the breast or stimulation of apoptosis)? Over 60 observational studies and two randomized trials provide evidence that the small but significant increase in risk appears with long-term current post-menopausal hormone use. The addition of a progestogen does not decrease the risk as seen with oestrogens alone and might increase the risk further. It is not clear whether there is a difference in risk with sequentially combined versus continuously combined HRT. Many questions nevertheless still remain. Is the risk increase limited to lean women only? What about risk-modifying factors such as alcohol use and a positive family history for breast cancer? Are tumours detected under HRT less aggressive, is there a better prognosis and is the mortality not increased while morbidity is? And is HRT contraindicated for women with a positive family history for breast cancer or in those women who have been treated for breast cancer? And finally, are there alternative options for these women?     

Mammary developmental fate and breast cancer risk

The ovarian hormones, estrogen and progesterone, play a pivotal role in normal and neoplastic development of the mammary gland. These hormones have a paradoxical role as long duration of estrogen and progesterone are associated with increased breast cancer risk, while short duration of pregnancy level doses are associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone, as well as pregnancy, have been extensively studied in animal models. Recent studies have demonstrated that these hormones induce alterations in gene expression in the mammary epithelial cells which persist for a long time after the hormones are withdrawn from the host. It is postulated that hormones induce a switch in mammary developmental fate which decreases the risk of breast cancer over the lifetime of the host. Some of the possible cellular pathways persistently altered by short term hormone exposure are a decrease in growth factors and an increase in apoptosis. The expression of these genes, in turn, may be affected by alterations in genes regulating chromatin remodeling. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. The current studies have moved this research area from the biological to the molecular realm and offer the potential for directing prevention efforts at specific molecular targets.     

Cancer in the older woman: diagnosis and prevention

Progestogens should be added to estrogen replacement therapy, not only to prevent endometrial cancer in women with a uterus, but also to reduce the risk of breast cancer in some women. Smoking should be discouraged to reduce the risk for both lung cancer and heart disease. Recommendations should be made to increase fiber intake to lessen the risk for carcinoma of the colon. Reducing fat intake also decreases risk for colon cancer, as well as carcinoma of the breast. Postmenopausal bleeding must be investigated for early diagnosis of endometrial cancer and, when endometrial hyperplasia is the finding, it should be treated with progestogens to prevent adenocarcinoma. The progestogen challenge test is recommended for all women with a uterus, and if bleeding occurs, the progestogen should be continued for 13 days each month. Use of mammograms and other diagnostic modalities should be increased to make the earliest possible diagnosis of breast cancer.     

Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system

The utility and safety of postmenopausal hormone replacement therapy has recently been put into question by large clinical trials. Their outcome has been extensively commented upon, but discussions have mainly been limited to the effects of estrogens. In fact, progestagens are generally only considered with respect to their usefulness in preventing estrogen stimulation of uterine hyperplasia and malignancy. In addition, various risks have been attributed to progestagens and their omission from hormone replacement therapy has been considered, but this may underestimate their potential benefits and therapeutic promises. A major reason for the controversial reputation of progestagens is that they are generally considered as a single class. Moreover, the term progesterone is often used as a generic one for the different types of both natural and synthetic progestagens. This is not appropriate because natural progesterone has properties very distinct from the synthetic progestins. Within the nervous system, the neuroprotective and promyelinating effects of progesterone are promising, not only for preventing but also for reversing age-dependent changes and dysfunctions. There is indeed strong evidence that the aging nervous system remains at least to some extent sensitive to these beneficial effects of progesterone. The actions of progesterone in peripheral target tissues including breast, blood vessels, and bones are less well understood, but there is evidence for the beneficial effects of progesterone. The variety of signaling mechanisms of progesterone offers exciting possibilities for the development of more selective, efficient, and safe progestagens. The recognition that progesterone is synthesized by neurons and glial cells requires a reevaluation of hormonal aging.     

Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast

The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen+progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women. Benign breast biopsies from 86 postmenopausal women were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of: 1) estrogen (E) alone; 2) estrogen+medroxyprogesterone acetate (E+P); or 3) no HRT. Compared with no HRT, the breast epithelium of women who had received either E+P or E alone had significantly higher PCNA proliferation indices, and treatment with E+P had a significantly higher index (PCNA and Ki67) than treatment with E alone. Breast epithelial density was significantly greater in postmenopausal women treated with E and E+P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E+P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E+P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk.     

An analysis of the effect of selection bias on the association of hormone replacement therapy and breast cancer risk

A sensitivity analysis was conducted to determine the impact on measures of effect of a suspected differential participation response rate between hormone replacement therapy (HRT) users and nonusers, among controls recruited to a population-based case-control study of breast cancer. The age-specific prevalence of current HRT use among controls was compared to data from the 1996 Canadian National Population Health Survey (NPHS). Control women identified as current HRT users were randomly re-sampled to replicate the prevalence of HRT use reported by the NPHS. Unconditional logistic regression was conducted to estimate odds ratios (OR) and 95 percent confidence intervals (CI) for the use of HRT and breast cancer risk before and after re-sampling. Multivariate adjusted ORs for breast cancer and estrogen-only and estrogen-progestin formulations were 0.76 (0.53-1.10) and 0.94 (95% CI: 0.64 - 1.38), respectively, using the original case-control controls and 0.99 (0.77-1.27) and 1.57 (95% CI: 1.02 - 2.40), respectively, following re-sampling of the controls. This sensitivity analysis illustrates the extent to which differential participation rates between HRT users and nonusers may affect estimates of measures of effect.     

Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women.

BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions. OBJECTIVE: To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile. METHODS: We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer. CONCLUSION: Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.     

Hormonersatztherapie und kardiovaskuläre Erkrankungen

Women enjoy a lower incidence of cardiovascular events than men, but this advantage is lost during the postmenopause. Epidemiological studies suggested that estrogen therapy for postmenopausal symptoms may exert protective effects against coronary heart disease (CHD); however, prospective, randomized clinical studies do not confirm cardiovascular protective effects of long-term treatment with estrogen/gestagen combinations. Instead, the risks for CHD, stroke, pulmonary embolism, and breast cancer increased, whereas the risks for hip fracture and colon carcinoma decreased. Phytoestrogens and synthetic steroids with estrogen action have not been shown to protect against cardiovascular disease, and raloxifene, a selective estrogen receptor modulator (SERM), has not demonstrated protection against CHD. Hormone replacement therapy in the postmenopause therefore cannot be recommended for cardiovascular risk reduction, but should only be initiated for severe postmenopausal symptoms.     

Hormone replacement therapy and endometrial,ovarian and colorectal cancer

Sex-steroid-related tumours in women are represented by breast cancer and endometrial cancer, but a possible relationship may exist between sex steroids and both ovarian and colon cancer. Unopposed oestrogen therapy is known to increase the risk of endometrial cancer and is appropriate only for hysterectomized women. In women with an intact uterus, an appropriate combination of oestrogen and progestin does not appear to increase-and may even decrease-the risk of endometrial cancer. Current users of HRT seem to benefit from a reduced risk for colon cancer. As for epithelial ovarian cancer, the present data are very conflicting. The association between replacement hormones and this malignancy seems to be stronger for unopposed oestrogen than for oestrogen-progestin treatment. Data available at the moment do not allow discriminating for dose, routes of administration, bioavailability and tissue effects of different compounds so that it is inappropriate to consider all forms of HRT jointly. The future of HRT in post-menopausal women lies in the individualization of the therapy based upon personal risk factors and characteristics.     

Prognostic indicators in node-negative early stage breast cancer.

With the increasing availability of screening mammography, more women are diagnosed as having breast cancers at an early, node-negative stage. The majority of these patients would be cured with total mastectomy or breast conservation treatment. However, about 30% of the patients would have recurrence of disease in distant sites. In recent randomized clinical trials, adjuvant systemic therapy has been shown to reduce the rate of recurrence in these patients. Proper selection of patients for adjuvant therapy is necessary to avoid exposing many patients with low risk of recurrence to treatments for whom the benefit is not justified by the toxicity and the cost. In this article, we review the clinical and pathologic prognostic factors in early stage, node-negative breast cancer patients, including tumor size, nuclear and histologic grades, estrogen and progesterone receptors, menopausal status, proliferative rate, HER-2/neu oncogene amplification, and cathepsin D level. Favorable prognostic factors include tumor size less than or equal to 2 cm, low nuclear and histologic grades, low S-phase fraction, diploid state, low cathepsin-D level, and positive estrogen and progesterone receptor status. The value of HER-2/neu oncogene overexpression is controversial, and further studies are needed to define its role as a prognostic factor in patients with node-negative breast cancer. Based on these prognostic factors, it is possible to identify subsets of patients who have a low risk of recurrence and would not benefit significantly from adjuvant systemic therapy.     

Carcinogenicity of antihypertensive therapy

Several studies have suggested that antihypertensive treatment may promote cancer through unknown mechanisms. Early retrospective studies implicated reserpine in breast cancer, but data from prospective studies and meta-analysis of several case-controlled studies showed only a weak association between reserpine and breast cancer which, although statistically significant, is of little clinical concern. Data from case-controlled studies and several cohort studies suggested an association between the use of a diuretic and the occurrence of renal cell cancer, particularly in women. A recent study showed an association between the use of a diuretic and the occurrence of colon cancer. Several prospective studies showed that treatment with atenolol may increase mortality from malignancy. However, other studies that analyzed data from several thousand patients could not confirm this association. In three prospective and a few case-controlled studies, angiotensin converting enzyme inhibitors were not associated with increased mortality from malignancy. In addition, a recent retrospective study showed that long-term use of angiotensin converting enzyme inhibitors had a protective effect against malignancy. Data from three large case-controlled studies and the combined data from eight randomized controlled studies and seven longitudinal studies showed a similar risk for malignancy among users and nonusers of calcium antagonists. Until further data from prospective clinical trials are available, we advise caution about longterm diuretic therapy in women. With regard to other antihypertensive drug classes, we suggest continuing the management of hypertension according to current treatment guidelines with little fear of any substantial cancer risk.     

Antiprogestins in breast cancer treatment: are we ready?

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. It is accepted that breast cancer is not a single disease, but instead constitutes a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Molecular gene expression studies have divided breast cancer into several categories, i.e. basal-like, ErbB2 enriched, normal breast-like (adipose tissue gene signature), luminal subtype A, luminal subtype B, and claudin-low. Chances are that as our knowledge increases, each of these types will also be subclassified. More than 66% of breast carcinomas express estrogen receptor alpha (ERα) and respond to antiestrogen therapies. Most of these ER+ tumors also express progesterone receptors (PRs), the expression of which has been considered as a reliable marker of a functional ER. In this paper we will review the evidence suggesting that PRs are valid targets for breast cancer therapy. Experimental data suggest that both PR isoforms (A and B) have different roles in breast cancer cell growth, and antiprogestins have already been clinically used in patients who have failed to other therapies. We hypothesize that antiprogestin therapy may be suitable for patients with high levels of PR-A. This paper will go over the experimental evidence of our laboratory and others supporting the use of antiprogestins in selected breast cancer patients.