Estrogen Receptor-negative Subtypes Research Articles

Targeted Next-Generation Sequencing Identifies Actionable Targets in Estrogen Receptor Positive and Estrogen Receptor Negative Endometriod Endometrial Cancer.

Endometrioid endometrial cancer (EEC) is the commonest form of endometrial cancer and can be divided into estrogen receptor (ER) positive and negative subtypes. The mutational profiles of EEC have been shown to aid in tailoring treatment; however, little is known about the differences between the gene mutation profiles between these two subtypes. This study aims to investigate the gene mutation profile in ER positive and negative EEC, and to further elucidate the role of WHSC1 mutations in this cancer. EEC and normal endometrial tissues were obtained from 29 patients and subjected to next-generation sequencing (NGS) using Ion Ampliseq Comprehensive Cancer PanelTM targeting 409 cancer related. A total of 741 non-synonymous alterations were identified from 272 genes in ER positive subtype while 448 non-synonymous variants were identified from 221 genes in ER negative subtype. PTEN is the most frequently altered gene in ER positive subtype (64%, 7/11) while ARID1A is the most frequently altered gene in ER negative subtype (50%, 4/8). We also identified alterations in ERRB3 (36%, 4/11), GNAS (36%, 4/11), and WHSC1 (27%, 3/11) in the ER positive subtype. WHSC1 R1126H and L1268P were shown to significantly increase cell viability, proliferation, migration, and survival. In addition, reduction in ER expression sensitized EEC-1 cell with WHSC1 L1268P mutant to Fulvestrant treatment. We revealed the mutational spectra of ER positive and ER negative EEC that could lead to better understanding of the biological mechanisms of endometrial cancer and may ultimately result in improvement of treatment options and patient prognosis.

Abstract 3543: Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents

Abstract The statin family of drugs target the mevalonate pathway and have been used for decades in the control of hypercholesterolemia, however recent evidence suggests these approved agents may also be useful as anti-cancer therapeutics (see our recent Nature Review Cancer article1). For example, statins can trigger tumor-specific apoptosis and two independent pre-op clinical trials in breast cancer, evaluating cholesterol-lowering doses of fluvastatin and atorvastatin, resulted in breast tumor shrinkage due to decreased growth and increased apoptosis. Our hypothesis is that statins have utility as anti-breast cancer agents. To maximize efficacy and speak to personalized medicine, our objectives are to develop biomarkers to distinguish which patients will benefit from the addition of statins to their treatment regimen and how best to use statins in combination with other agents to augment anti-tumor efficacy. To identify biomarkers of statin sensitivity we evaluated fluvastatin activity across a panel of BCa cell lines and showed that the basal, estrogen receptor-negative subtype were significantly sensitive to statin-induced apoptosis. As this included the difficult-to-treat triple negative BCa (TNBCa) we have extended this work and further evaluated a panel of TNBCa cell lines for statin sensitivity. From these results we are identifying features associated with robust apoptosis in response to statin exposure. To identify how best to use statins, we conducted two unbiased screens and have shown that blocking the restorative feedback response to statin exposure potentiates statin-induced apoptosis. This is reversible with exogenous mevalonate, reinforcing that this is an on-target effect. We also identified another approved agent, dipyridamole, as able to potentiate the anti-cancer activity of statins. Mechanistically we have shown that dipyridamole blocks the feedback response to statin exposure. We have extended these studies and shown that the combination of statins and dipyridamole is effective against TNBCa both in vitro and in vivo. Thus, we provide essential pre-clinical data to support the further evaluation of statins and dipyridamole in BCa. Reference: Mullen, P.J. et al. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 16, 718-731 (2016). Citation Format: Jenna van Leeuwen, Aleksandra Pandyra, Carolyn Goard, Peter J. Mullen, Rosemary Yu, Linda Z. Penn. Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3543. doi:10.1158/1538-7445.AM2017-3543

Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated With Estrogen Receptor-Negative Subtypes and Poor Prognosis

Both BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n=1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers.

Incidence of Breast Cancer With Distant Involvement Among Women in the United States, 1976 to 2009

Evidence from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database suggests that the incidence of advanced breast cancer in young women is increasing. To quantify this trend and analyze it as a function of stage at diagnosis, race/ethnicity, residence, and hormone receptor status. Breast cancer incidence, incidence trends, and survival rates as a function of age and extent of disease at diagnosis were obtained from 3 SEER registries that provide data spanning 1973-2009, 1992-2009, and 2000-2009. SEER defines localized as disease confined to the breast, regional to contiguous and adjacent organ spread (eg, lymph nodes, chest wall), and distant disease to remote metastases (bone, brain, lung, etc). Breast cancer incidence trends in the United States. In the United States, the incidence of breast cancer with distant involvement at diagnosis increased in 25- to 39-year-old women from 1.53 (95% CI, 1.01 to 2.21) per 100,000 in 1976 to 2.90 (95% CI, 2.31 to 3.59) per 100,000 in 2009. This is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07% per year (95% CI, 1.57% to 2.58%; P < .001) over the 34-year interval. No other age group or extent-of-disease subgroup of the same age range had a similar increase. For 25- to 39-year-olds, there was an increased incidence in distant disease among all races and ethnicities evaluated, especially non-Hispanic white and African American, and this occurred in both metropolitan and nonmetropolitan areas. Incidence for women with estrogen receptor-positive subtypes increased more than for women with estrogen receptor-negative subtypes. Based on SEER data, there was a small but statistically significant increase in the incidence of breast cancer with distant involvement in the United States between 1976 and 2009 for women aged 25 to 39 years, without a corresponding increase in older women.

Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy

Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported "breast intrinsic" gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor-negative subtypes. The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.