Does Microenvironment Contribute to the Etiology of Estrogen Receptor–Negative Breast Cancer?

Abstract

What dictates the prevalence of certain types of breast cancer, which are classified by markers, particularly estrogen receptor (ER), expression profiles such as basal or luminal, and genetic alterations such as HER2 amplification, in particular populations is not well understood. It is increasingly evident that microenvironment disruption is highly intertwined with cancer progression. Here, the idea that microenvironment shapes the course of carcinogenesis, and hence breast cancer subtype, is discussed. Aggressive, basal-like, ER-negative breast tumors occur in younger women, African-American women, women who carry BRCA1 mutation, and women exposed to ionizing radiation. Recent experimental studies using ionizing radiation, a well-documented environmental exposure, suggest that certain processes in the microenvironment strongly favor the development of ER-negative tumors. Understanding the contribution of tissue microenvironment during carcinogenesis could lead to prevention strategies that are personalized to age, agent, and exposure to reduce the risk of aggressive breast cancer.

Occupational Exposure to Ionizing Radiation and Risk of Breast Cancer in Western Australia

“…Supporting results of an increased risk of HER2-positive breast cancer after exposure to ionizing radiation were also found in several other recent studies. 24,25,28,29 In a review by Barcellos-Hof, 26 it was postulated that radiation predisposes ER-negative breast tumors, which is in contrast to our results where occupational exposure to ionizing radiation led to a slight increase in ER-positive breast cancer.…”

“…23 Gene amplification of human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER)-negative breast tumors are seen in breast cancers caused by radiation exposure. [24][25][26][27][28][29] Human epidermal growth factor receptor 2 is involved in pathways that regulate cell growth and proliferation. 30 Estrogens are believed to affect the pathological processes initiated by ionizing radiation in turning mammary gland cells into malignant cells.…”

Complexities of androgen receptor signalling in breast cancer

“…ERa-negative breast cancers comprise w30% of all breast cancers and are typically more aggressive and have poor survival prognoses compared with ERa-positive tumours (Barcellos-Hoff 2013). AR expression in ERa-negative breast cancer is correlated with a lower Nottingham grade and apocrine differentiation (Niemeier et al 2010).…”

A positive role of DBC1 in PEA3-mediated progression of estrogen receptor-negative breast cancer

“…1,2 Among the breast cancer subtypes, estrogen receptor α (ER)-negative breast cancers are more aggressive and metastatic than ER-positive breast cancers and unresponsive to anti-estrogen therapy. 3 Elevated expression of human epidermal growth factor receptor 2 (HER2), which activates the mitogen-activated protein kinase (MAPK) signaling pathways, is also associated with aggressiveness and metastasis in breast cancer. 4 It has been shown that ER-positive and -negative breast cancers exhibit large differences in their gene expression profiles.…”