Benefits and risks of menopausal estrogen and/or progestin hormone use,

Current evidence is reviewed here on risks and benefits of estrogen and progestin use by peri- and postmenopausal women in relation to the following conditions: endometrial cancer, breast cancer, osteoporosis, and coronary artery disease (CAD). On balance, estrogen therapy appears to be beneficial for menopausal women, as it probably reduces the risks of CAD and osteoporosis, two of the major causes of mortality and morbidity. Although unopposed estrogen therapy increases the risk of endometrial cancer, that cancer is relatively rare and is not fatal in the vast majority of cases associated with estrogen use. Definitive conclusions about the relation of menopausal estrogens to breast cancer cannot be drawn due to inconsistent evidence to date. Although evidence from randomized controlled trials is lacking, biochemical and clinical evidence suggest that progestin supplementation is associated with a reduction in endometrial cancer risk in women taking menopausal estrogens. Progestin supplementation also may augment the beneficial effects of estrogens in providing protection against osteoporosis, although this effect is not yet well established. There is little direct evidence bearing on the relation of menopausal progestins to breast cancer. Although studies of CAD per se are lacking at present, progestins probably unfavorably alter lipoprotein profiles, thereby increasing a user's risk of CAD. Given the relatively high incidence and mortality of CAD in postmenopausal women, any negative effects on CAD risk could potentially counterbalance beneficial effects on other causes. We conclude that estrogen replacement therapy is of potential benefit to postmenopausal women, but that the question of progestin supplementation requires further study, particularly for CAD risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27382/1/0000412.pd

Characteristics Associated With Recurrence Among Women With Ductal Carcinoma In Situ Treated by Lumpectomy

BACKGROUND: Clinical and histopathologic characteristics that may predict risks of recurrence in women with ductal carcinoma in situ (DCIS) have not been consistently identified. We identified factors associated with recurrence as DCIS versus invasive breast cancer and determined the 5-year absolute risks of recurrence as a function of these factors. METHODS: We conducted a population-based cohort study among 1036 women in the San Francisco Bay Area who were aged 40 years or older when diagnosed with DCIS and treated by lumpectomy alone from January 1983 through December 1994. Standardized pathology reviews were conducted to determine disease recurrence, defined as DCIS or invasive breast cancer diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a distant site more than 6 months after the initial diagnosis and treatment of DCIS. Conditional logistic regression models were used to determine factors associated with recurrence. All statistical significance tests were two-sided. RESULTS: During a median follow-up of 77.9 months, 209 women (20.2%) experienced a recurrence. Overall, the 5-year risks of recurrence as invasive cancer and as DCIS were 8.2% (95% confidence interval [CI] = 6.6% to 9.8%) and 11.7% (95% CI = 9.9% to 13.3%), respectively. The 5-year risks of recurrence as invasive cancer and as DCIS were 4.8% (95% CI = 3.7% to 6.8%) and 4.8% (95% CI = 3.8% to 5.8%), respectively, for women with low-nuclear-grade DCIS; 11.8% (95% CI = 9.9% to 14.1%) and 17.1% (95% CI = 15.5% to 18.7%), respectively, for women with high-nuclear-grade DCIS; 11.6% (95% CI = 11.3% to 12.0%) and 8.6% (95% CI = 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI = 6.2% to 7.1%) and 14.1% (95% CI = 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus > or = 10 mm disease-free); and age 40-49 years at diagnosis (versus > or =50 years) were associated with recurrence as DCIS. CONCLUSIONS: Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence, compared with women with low-nuclear-grade or mammographically detected DCIS, and may be appropriate candidates for additional treatment

Characteristics Associated With Recurrence Among Women With Ductal Carcinoma In Situ Treated by Lumpectomy

BACKGROUND: Clinical and histopathologic characteristics that may predict risks of recurrence in women with ductal carcinoma in situ (DCIS) have not been consistently identified. We identified factors associated with recurrence as DCIS versus invasive breast cancer and determined the 5-year absolute risks of recurrence as a function of these factors. METHODS: We conducted a population-based cohort study among 1036 women in the San Francisco Bay Area who were aged 40 years or older when diagnosed with DCIS and treated by lumpectomy alone from January 1983 through December 1994. Standardized pathology reviews were conducted to determine disease recurrence, defined as DCIS or invasive breast cancer diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a distant site more than 6 months after the initial diagnosis and treatment of DCIS. Conditional logistic regression models were used to determine factors associated with recurrence. All statistical significance tests were two-sided. RESULTS: During a median follow-up of 77.9 months, 209 women (20.2%) experienced a recurrence. Overall, the 5-year risks of recurrence as invasive cancer and as DCIS were 8.2% (95% confidence interval [CI] = 6.6% to 9.8%) and 11.7% (95% CI = 9.9% to 13.3%), respectively. The 5-year risks of recurrence as invasive cancer and as DCIS were 4.8% (95% CI = 3.7% to 6.8%) and 4.8% (95% CI = 3.8% to 5.8%), respectively, for women with low-nuclear-grade DCIS; 11.8% (95% CI = 9.9% to 14.1%) and 17.1% (95% CI = 15.5% to 18.7%), respectively, for women with high-nuclear-grade DCIS; 11.6% (95% CI = 11.3% to 12.0%) and 8.6% (95% CI = 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI = 6.2% to 7.1%) and 14.1% (95% CI = 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus > or = 10 mm disease-free); and age 40-49 years at diagnosis (versus > or =50 years) were associated with recurrence as DCIS. CONCLUSIONS: Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence, compared with women with low-nuclear-grade or mammographically detected DCIS, and may be appropriate candidates for additional treatment

Characteristics Associated With Recurrence Among

ively, for women with high-nuclear-grade DCIS; 11.6% (95% CI # 11.3% to 12.0%) and 8.6% (95% CI # 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI # 6.2% to 7.1%) and 14.1% (95% CI # 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus >10 mm disease-free); and age 40 -- 49 years at diagnosis (versus >50 years) were associated with recurrence as DCIS. Conclusions: Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with highnuclear -grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an inv

Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression

The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Although the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 downregulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo, resulting in marked reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies