Annals of Surgical Oncology 06/2010; 17(6):1485-6. · 4.17 Impact Factor
Plastic and reconstructive surgery 04/2010; 125(4):173e-174e. · 2.74 Impact Factor
ABSTRACT: Loss of estrogen receptor α ERα in breast cancer correlates with a more aggressive, tamoxifen resistant phenotype. ERα-negative
tumors often display overexpression or amplification of growth factor receptors of the erbB family, particularly EGFR and
erbB-2, and consequently, elevated growth factor signaling and resultant MAP kinase (ERK) activity. We have previously shown
that overexpression/hyperactivation of EGFR or erbB-2, or the downstream effectors Raf or MEK, in ERα+, estrogen-dependent
MCF-7 cells results in the acquisition of estrogen-independence and loss of ERα expression. We have shown that the common
downstream effector of ERα downregulation in all our model cell lines is hyperactive MAPK and that inhibition of this hyperactive
MAPK restores ERα expression. Microarray expression profiling of these hyperactive MAPK model cell lines revealed a hyperactive
MAPK signature that correlates with ERα-breast cancer and not ERα+ breast cancer. We have more recently extended these observations
to established ERα-breast cancer cell lines and primary cultures from ERα-breast tumor specimens. Inhibition of MAPK in these
ERα-breast cancer cells restores ERα expression and associated with this re-expression of ERα is the acquisition of anti-estrogen
responses. These data demonstrate the dynamic nature of ERα expression in breast cancer cells and the ability to impact ERα
expression by altering cellular signaling pathways. Further, they suggest a potential novel therapeutic strategy for ERα-breast
cancer: inhibition of MAPK activity to restore both ERα expression and anti-estrogen responses.
01/2009: pages 39-62;
ABSTRACT: In breast cancer, the presence of estrogen receptor alpha (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERalpha correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ERalpha expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERalpha(-) breast cancer cell lines and tumors results in reexpression of ERalpha, and further, if reexpression of ERalpha in these ERalpha(-) tumors and cell lines could restore antiestrogen responses.
Established ERalpha(-) breast cancer cell lines, ERalpha(-) breast tumors, and tumor cell cultures obtained from ERalpha(-) tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ERalpha was used to assess the reexpression of ERalpha in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells.
Inhibition of MAPK activity in ERalpha(-) breast cancer cell lines results in reexpression of ERalpha; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERalpha can now mediate an antiestrogen response in a subset of these ERalpha(-) breast cancer cell lines. Treatment of ERalpha(-) tumor specimens with MAPK inhibitors results in restoration of ERalpha mRNA, and similarly in epithelial cultures from ERalpha(-) tumors, MAPK inhibition restores both ERalpha protein and antiestrogen response.
These data show both the possibility of restoring ERalpha expression and antiestrogen responses in ERalpha(-) breast cancer and suggest that there exist ERalpha(-) breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.
Clinical Cancer Research 01/2008; 13(23):7029-36. · 7.74 Impact Factor
ABSTRACT: Recent data have demonstrated that benefit from adjuvant tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) is limited to estrogen receptor (ER)-positive lesions. The objective of the current study was to correlate clinicopathologic features of DCIS with ER expression and the impact of this information on tamoxifen counseling.
Women with DCIS who were treated from 2001 to 2004 were evaluated. Routine ER staining was initiated in January 2003.
Ninety-four women (mean age, 57.6 years) were analyzed. The mean DCIS size was 0.98 cm. ER-staining was performed in 55 lesions, and 76% were ER-positive. All Grade 1 and 2 DCIS lesions were ER-positive, compared with 54% of high-grade lesions (P<.001); no other clinicopathologic feature significantly predicted ER status. Overall, 58 patients (62%) were offered tamoxifen, and the rates were similar for the pre-ER and post-ER staining periods. In the pre-ER staining period, surgical treatment and grade were associated with offering tamoxifen (75% of patients who underwent breast conservation vs. 40% of patients who underwent mastectomy; P = .03; 78% of patients with Grade 1 or 2 lesions vs. 45% of patients with Grade 3 lesions; P = .04). In the post-ER staining period, however, only ER status was correlated significantly with offering tamoxifen (71% of patients with ER-positive lesions vs. 31% of patients with ER-negative lesions; P = .01). Approximately 66% of patients who were offered tamoxifen agreed to treatment (approximately 33% of the total DCIS study sample). No clinicopathologic features predicted for tamoxifen acceptance by patients in either the pre-ER or post-ER staining periods.
Seventy-five percent of DCIS lesions were ER-positive. ER staining significantly influenced the likelihood that clinicians would offer tamoxifen to patients with DCIS, but it had no impact on whether patients accepted treatment.
Cancer 05/2006; 106(10):2113-8. · 4.77 Impact Factor
ABSTRACT: Incidence and mortality rates for cancers vary by ethnic background and patient age. Accrual of diverse patient populations to cancer clinical trials is essential in order to ensure that findings related to new management strategies can be generalized. The goal of this study was to evaluate accrual patterns for patients participating in the American College of Surgeons Oncology Group (ACOSOG) cancer protocols. Ethnic diversity among clinical trial investigators may also influence accrual patterns, so the ethnic background of the ACOSOG membership was also evaluated.
Demographics for the patients registered on ACOSOG breast, thoracic, and colorectal clinical trials were evaluated and compared with data on the general population and the cancer population in the United States. Accrual patterns for patients from other reported cancer clinical trials were also presented, and the self-reported ethnic distribution of the ACOSOG membership was analyzed.
Distribution of African Americans, Hispanic Americans, and Asian Americans to the ACOSOG breast and colorectal clinical trials was relatively proportionate to the cancer population. African Americans were underrepresented in the thoracic clinical trials, and this disparity was partially offset by data on the proportion of African Americans with stage-eligible lung cancer. Accrual rates for patients age 65 years and older were better than those reported by most other clinical trialists.
Elderly patients are successfully recruited into surgical clinical trials, and this will provide important data for future analyses regarding cancer outcomes in this growing population of cancer patients. Aggressive outreach to minority-ethnicity cancer patients for accrual into clinical trials should continue.
Journal of the American College of Surgeons 11/2004; 199(4):644-51. · 4.55 Impact Factor